Дисертації з теми "KIF5A"
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1
Lin, Raozhou, and 林饒洲. "Kif5b interaction with NMDA receptors regulates neuronal function." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/208429.
Повний текст джерелаАнотація:
Intracellular transportation is an essential cellular event controlling neuronal development, morphology, function and survival. Kinesin-1 is the molecular motor conveying cargo along microtubule by utilizing the chemical energy from ATP hydrolysis. This motor consists of two heavy chains and two light chains. Both heavy and light chains are responsible for cargo bindings. There are three kinesin-1 heavy chains in eukaryotic cells. Kif5a and Kif5c are neuronal specific, while Kif5b is ubiquitously expressed. Kif5b carries various cargos essential for neuronal functions, and the early embryonic death of Kif5b null mice suggests the importance of Kif5b in vivo.
N-methyl-d-aspartate receptors (NMDARs) are glutamate elicited channel, which is permeable to calcium and crucial for synaptic plasticity in the central nervous system. NMDARs are heteromeric assemblies consisting of NR1, NR2 and NR3 subunits. These transmembrane subunits contain three parts. Other than the transmembrane domain, the extracellular domain serves as the ligand binding site while the intracellular domain interacts with various partners regulating downstream signaling and receptor trafficking. Synaptic NMDAR activation regulates synaptic plasticity, while extrasynaptic NMDAR activation leads to excitotoxicity.
In this project, I find that kinesin-1 directly interacts with NMDAR subunit, NR1, NR2A and NR2B in vivo. NMDAR colocalizes with kinesin-1 in the cell body and neurites. By GST-pull-down assays with different Kif5b fragments, the cytoplasmic domains of NR1, NR2A and NR2B are found to directly bind with Kif5b via a Kif5b C-terminal region independent of kinesin light chains.
To examine the role of Kif5b in NMDAR trafficking, dominant negative Kif5b fragments are expressed in cell lines together with NR1-1a and GFP-NR2B. Overexpression of dominant negative Kif5b significantly disrupts GFP-NR2B forward trafficking and prevents it from entering into Golgi apparatus. Furthermore, the surface NR1 and NR2B levels are significantly reduced whilst the NR2A levels are not affected in Kif5b+/- mice in which the Kif5b protein level is reduced by 50% compared with the wild-type littermates. Consistent with this observation, the NR1 and NR2B levels are decreased in fractions containing synaptosomal membrane but not the one containing only postsynaptic densities, suggesting that the extrasynaptic NMDAR levels are affected in Kif5b+/- mice.
NMDARs are highly permeable to calcium while activated, thereby activating neuronal nitric oxide synthases (nNOS) to produce nitric oxide (NO). It is found that NMDA triggered calcium influx is perturbed in Kif5b+/- neurons, while the synaptic NMDA receptor mediated calcium influx is normal. In Kif5b+/- slices, the production of NO reduces significantly. Calcium ionophore, A23187, rescue this NO defect, indicating insufficient supply of calcium as the main contribution to this defect. Therefore, Kif5b-dependent extrasynaptic localization of NMDA receptors mediates calcium influx upon NMDA stimulation and controls NO production.
In the summary, above results suggest kinesin-1 as a novel motor involving in NMDA receptor trafficking. This interaction may contribute to the extrasynaptic distribution of NMDARs. By regulating NO production through interaction with NMDARs, Kif5b may mediate neuronal survival in cerebral ischemia and certain aggressive behaviors. This provides a novel target for therapy development against stroke and schizophrenia.published_or_final_version
Biochemistry
Doctoral
Doctor of Philosophy
2
Wang, Jing, and 王景. "The study of KIF5B-mediated intracellular transport in neurons." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41633763.
Повний текст джерела
3
Wang, Jing. "The study of KIF5B-mediated intracellular transport in neurons." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41633763.
Повний текст джерела
4
D'Amico, Eva. "Etude des effets de l'inactivation de Kif3a dans les cellules thyroïdiennes." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209643.
Повний текст джерелаАнотація:
Afin d’assurer les échanges entre ses différents organites, la cellule eucaryote dispose d’un système ingénieux de trafic vésiculaire intracellulaire. Le transport directionnel de divers cargos tels que des organites membranaires et des complexes protéiques est assuré par des moteurs moléculaires auxquels appartiennent les protéines de la superfamille des kinésines (également appelées KIF pour KInesin Family). Celles-ci se servent des microtubules comme rails et se déplacent vers leur extrémité positive. Parmi elles, la kinésine II est composée de KIF3A et KIF3B, deux protéines motrices et de KAP3, une protéine de liaison au cargo à véhiculer. Ce moteur moléculaire est connu pour participer à l’assemblage du cil primaire à la surface des cellules ainsi qu’au trafic plus conventionnel tel que l’acheminement de protéines à la membrane. Afin d’étudier le rôle précis de la kinésine II dans la glande thyroïde, nous avons invalidé spécifiquement le gène Kif3a dans cet organe chez la souris. Bien que cette inactivation ait conduit à un développement complet du tissu thyroïdien, les souris invalidées présentent une hypothyroïdie congénitale caractérisée par des concentrations sériques élevées de TSH et basses de T4. Par la suite, nous avons mis en évidence une expression fortement diminuée du transporteur d’iodure NIS chez ces souris, causant une déficience en iodure intracellulaire, une iodation insuffisante de la thyroglobuline et une sécrétion anormale de l’hormone T4 dans la circulation sanguine. De plus, ex vivo, nous avons montré que la réponse à la TSH en terme d’AMPc est altérée dans la thyroïde de ces souris. Ces observations nous ont permis d’émettre l’hypothèse que l’invalidation du gène Kif3a spécifiquement dans la glande thyroïde mène à une anomalie dans la voie de signalisation du récepteur de la TSH, en amont de la production d’AMPc. Finalement, in vitro, par l’utilisation de cellules Kif3a-/-, nous avons analysé l’expression à la membrane plasmique et la réponse à un agoniste du récepteur β2 adrénergique, un membre de la même sous-famille de récepteurs couplés aux protéines G que le récepteur de la TSH. De cette façon, nous avons obtenu des données indiquant que le transport de ce récepteur à la surface cellulaire était altéré en l’absence de Kif3a.
Au vu de ces éléments et de ceux de la littérature, nous suggérons que la kinésine II, et plus particulièrement sa sous-unité KIF3A, joue un rôle important dans le transport du récepteur de la TSH nouvellement synthétisé vers la membrane basale de la cellule de la thyroïde.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished
5
Röhlk, Christian. "Characterization of conventional kinesins Kif3 and Kif5 from Dictyostelium discoideum." Diss., lmu, 2007. http://nbn-resolving.de/urn:nbn:de:bvb:19-73948.
Повний текст джерела
6
Zhu, Guixia, and 朱貴霞. "Study of the function of Kinesin-1 (KIF5B) in long bone development." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B41757919.
Повний текст джерела
7
Gan, Huiyan, and 甘慧妍. "Understanding the role of KIF5B in long bone development and chondrocyte cytokinesis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/211554.
Повний текст джерелаАнотація:
Kinesins are motor proteins responsible for the anterograde transport on microtubules. Kinesin-1 is the first characterized kinesin, and it consists of two heavy chains and two light chains. KIF5B is a form of Kinesin-1 heavy chains that is ubiquitously expressed in mammals. The head domain of KIF5B is responsible for ATP-dependent mechanical movement along microtubules, while the tail region is well-known for its interaction with cell specific cargos. Recent studies reveal a second microtubule binding site in the tail, suggesting special functions of KIF5B in microtubule sliding and bundling.
To understand the role of KIF5B in long bone development, a conditional knockout mouse model was generated, in which Kif5b is deleted in early limb mesenchyme using Prx1-cre/LoxP mediated recombination. Unlike Col2a1-cre directed Kif5b knockout in chondrocytes, the expression of Prx1-cre in limb mesenchyme results in Kif5b knockout in both chondrocyte and osteoblast lineages. The Prx1-cre mediated Kif5b conditional knockout mice develop malformed long bones characterized by their bowed shape, shortened length and multiple fractures, which reflects a combination of defects in bone matrix and growth plate. The mutant mice demonstrate impaired bone matrix formation, as indicated by both collagen density reduction and collagen matrix disorganization. Also, the growth plate does not retain its normal organization, and the hypertrophic zone is absent. The KIF5B deficient chondrocytes not only lose planar cell polarity, but also undergo early apoptosis and fail in terminal differentiation. Interestingly, the binucleation rate is significantly increased in these chondrocytes, suggesting a severe cytokinesis defect. Besides, the intracellular retention of extracellular matrix (ECM) molecules and the uneven distribution of ECM in the cartilage imply both blockage and inappropriate direction of secretion.
Cytokinetic defect in chondrocytes is closely associated with growth plate abnormality and growth retardation. In Kif5b knockout chondrocytes, cytokinetic defect is also one of the earliest and principal phenotypes. Therefore the underlying mechanism of cytokinetic defect was further investigated at cellular level. Since Kif5b knockout chondrocytes cannot survive in primary culture, RNA interference approach was adopted to generate a Kif5b-knockdown chondrogenic cell line. As expected, the Kif5b knockdown cells demonstrate cytokinetic defects characterized by increased binucleation rate and prolonged cytokinesis phase. In control cells, KIF5B becomes concentrated in the midbody during cytokinesis, and the midbody organization is disrupted in Kif5b knockdown cells. Furthermore, transient expression of full-length KIF5B significantly reduces the binucleation rate of these KIF5B deficient cells, whereas over-expression of a truncated KIF5B (without microtubule binding sites in tail region) cannot rescue the defect. Additionally, KIF5B is found to interact with midbody components PRC1 and Aurora B kinase by GST pull-down assay.
This study demonstrates the multiple functions of KIF5B in long bone development and emphasizes its significant role as a key modulator in chondrocyte cytokinesis. More importantly, the study also brings new insights into the mechanisms of cytokinesis: we propose that KIF5B may participate in cytokinesis by regulating the midbody organization and stability via microtubule bundling and transporting or anchoring important components to the midbody.published_or_final_version
Biochemistry
Doctoral
Doctor of Philosophy
8
Zhu, Guixia. "Study of the function of Kinesin-1 (KIF5B) in long bone development." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B41757919.
Повний текст джерела
9
Lin, Yangjun, and 林扬骏. "Kif5b may play a role in impairing mouse memory : a behaviour and cellular study." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193575.
Повний текст джерелаАнотація:
Alzheimer's Disease is one of the most fearsome diseases worldwide. The study of Alzheimer's Disease (AD) is broad and many have focused on investigating the various proteins involved in neurons. A popular hypothesis of the cellular mechanism of AD is the accumulation of beta-Amyloid. Kinesin is a large group of motor proteins, which plays an extensive role in mitosis and intracellular cargo transport, including that of the Amyloid Protein Precursor. In the present study we have performed fear conditioning behaviour tests on Kif5b conditional knockout (CKO) mouse. Kif5b CKO mouse shows an impair contextual memory compared to the wild type, but does not display an impaired auditory memory. Heterozygous Kif5b knock out mouse shows no significant difference to the wild type. The study has also generated Kif5b fragments and used them to pull-down proteins in mouse brain lysate. The study has identified Clathrin and alpha-Adaptin as binding partners of Kif5b in mouse neuronal cells. The binding domain of Kif5b for these proteins is between amino acid residue 891-935. Finally this study has made a number of recommendations for further study.published_or_final_version
Biochemistry
Master
Master of Medical Sciences
10
Millington, Grethel. "Primary Cilia-dependent Gli Processing in Neural Crest Cells is Required for Early Tongue Development." University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1479815997983138.
Повний текст джерела
11
Broix, Loïc. "Compréhension des mécanismes physiopathologiques des malformations du développement cortical associées à des mutations dans les gènes KIF2A et NEDD4L." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB103/document.
Повний текст джерелаАнотація:
Les malformations du développement cortical (MDC) résultent d’altérations au niveau de différentes étapes de la corticogénèse telles que la prolifération, la migration et la différenciation neuronale et sont généralement associées à des épilepsies pharmaco-résistantes et à des déficiences intellectuelles sévères. Les causes génétiques des MDC restent encore inconnues dans de nombreux cas, nous avons donc réalisé le séquençage de l’exome entier de nombreux patients présentant des MDC et les analyses ont permis de mettre en évidence l’implication des gènes KIF2A et NEDD4L dans les MDC. Dans le cadre de ma thèse, nous proposons de focaliser sur les conséquences cellulaires et neurodéveloppementales résultant des mutations dans les gènes KIF2A et NEDD4L retrouvées chez les patients atteints de MDC. KIF2A code pour une kinésine-13 qui a pour fonction de réguler la dynamique des microtubules (MT) via son activité MT dépolymérase ATP-dépendante aux niveaux des extrémités des MT. L’approche basée sur la technique d’électroporation in utero nous a permis de mettre en évidence le rôle crucial joué par KIF2A dans la régulation de la neurogénèse, la migration neuronale et le positionnement des neurones dans le cortex. En particulier, nos données révèlent que l’expression des mutants KIF2A responsables de MDC entraîne une augmentation du nombre de cellules à l’état de progéniteurs qui est conséquente à un allongement du temps passé dans le cycle cellulaire. Nos premières données cellulaires et au cours du développement montrent que l’expression des mutants KIF2A induit des altérations dans l’intégrité du fuseau mitotique, dans la progression mitotique et également une localisation anormale de KIF2A au niveau du cil primaire. NEDD4L code pour une E3 ubiquitine ligase qui joue un rôle dans l’ubiquitination de nombreux substrats permettant la régulation de leur dégradation et de leur localisation subcellulaire. Dans un premier temps, nos données cellulaires ont montré que les mutants associées à des MDC ont une sensibilité accrue pour la dégradation par le protéasome. De plus, l’approche d’électroporation in utero a permis de montrer que l’expression des mutants NEDD4L ainsi qu’un excès de NEDD4L WT dérégulent la neurogenèse, le positionnement des neurones et le processus de translocation terminal. Des études complémentaires, incluant le traitement à la rapamycine, ont révélé qu’un excès de NEDD4L WT mène à la dérégulation des voies de signalisations mTORC1 et Dab1 tandis que l’expression des mutants est associée à une dérégulation des voies mTORC1 et Akt. L’ensemble de ces résultats renforce donc dans un premier temps l’importance des protéines liées aux MT dans le développement cortical en décrivant le rôle crucial de la kinésine KIF2A dans des mécanismes tels que la dynamique de migration neuronale et dans la régulation du cycle cellulaire des progéniteurs neuronaux. D’autre part, nous fournissons également de nouvelles données permettant de mieux comprendre le rôle critique de NEDD4L dans la régulation des voies mTOR et de leurs contributions dans le développement corticalMalformations of cortical development (MCD) result from alterations in different stages of corticogenesis such as proliferation, migration and neuronal differentiation, and are generally associated with drug-resistant epilepsy and severe intellectual disabilities. The genetics causes of MCD remain largely unknown, we have thus performed the whole-exome sequencing of many patients with MCD and reported the identification of multiple pathogenic missense mutations in KIF2A and NEDD4L genes. Within the frame of my thesis project, we propose to focus on the cellular and neurodevelopmental consequences resulting from KIF2A and NEDD4L mutations shown to be involved in MCD. KIF2A is a member of the kinesin-13 family, which rather than regulating cargos transport along microtubules (MT), regulates MT dynamics by depolymerizing MTs. The in utero electroporation approach allowed us to highlight the crucial role of KIF2A in the regulation neurogenesis, neuronal migration and the neuronal positioning in the cortex. Particularly, our data show that the expression of the KIF2A mutants involved in MDC lead to an increase in the number of cells in proliferative state which is a consequence of a prolonged time spent in the cell cycle. Our first cellular data and during development show that the expression of pathogenic KIF2A mutations induce alterations in the mitotic spindle integrity, in the mitotic progression and also an abnormal localization of KIF2A in the primary cilium. NEDD4L encodes a member of the NEDD4 family of HECT-type E3 ubiquitin ligases known to regulate the turnover and function of a number of proteins involved in fundamental cellular pathways and processes. Firstly, cellular and expression data showed sensitivity of MCD-associated mutants to proteasome degradation. Moreover, the in utero electroporation approach showed that PNH-related mutants and excess wild-type NEDD4L affect neurogenesis, neuronal positioning and terminal translocation. Further investigations, including rapamycin-based experiments, found differential deregulation of pathways involved. Excess wild-type NEDD4L leads to disruption of Dab1 and mTORC1 pathways, while MCD-related mutations are associated with deregulation of mTORC1 and AKT activities. Altogether, these results reinforce the importance of MT-related proteins in cortical development describing the crucial role of KIF2A kinesin in mechanisms such as neuronal migration dynamics and neuronal progenitor’s cell cycle regulation. On the other hand, we also provide new data to better understand the critical role of NEDD4L in the regulation of mTOR pathways and their contributions in cortical development
12
Súarez, López Lucía. "Condensin complex and Molecular Motor KIF4A, new players in CRC under WNT signalling regulation = Papel del Complejo Condensina y el Motor Molecular KIF4A en el Cáncer Colorrectal como nuevas dianas de la vía de señalización Wnt." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/126298.
Повний текст джерелаАнотація:
Durante la división celular, el ADN debe estructurarse en cromosomas para asegurar un correcto reparto de la información genética a las dos células hijas. El complejo condensina, junto con el motor molecular KIF4A, son los encargados de dar estructura y estabilidad a los cromosomas. En este estudio hemos demostrado que estas proteínas se encuentran frecuentemente sobre-expresadas en el cáncer colorrectal y que esta sobre-activación se debe a que están bajo la regulación de la vía Wnt. Esta vía de señalización, fundamental para el mantenimiento de a homeóstasis del epitelio intestina, está íntimamente ligada a la tumorogénesis colorrectal, ya que su hiperactivación aberrante está presente en un 85% de casos de cáncer colorectal. Hemos estudiado además la posible implicación de KIF4A en el proceso tumorogénico y hemos visto que está asociada a proliferación, invasión, mecanismos de diferenciación celular y respuesta a daño al ADN. Por último, se han identificado los niveles altos de expresión de KIF4A como marcador de mal pronóstico en casos avanzados de cáncer colorrectal.
13
Montenegro-Garreaud, Ximena, Adam W. Hansen, Michael M. Khayat, Varuna Chander, Christopher M. Grochowski, Yunyun Jiang, He Li, et al. "Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases." John Wiley and Sons Inc, 2020. http://hdl.handle.net/10757/655505.
Повний текст джерелаАнотація:
KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.National Institutes of Health
Revisión por pares
14
Barry, Joshua. "Function and Mechanism of Polarized Targeting of Neuronal Membrane Proteins." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373971273.
Повний текст джерела
15
Lafrance, Amina. "La zone frontale des Mauritanides méridionales. Lithostratigraphie, sédimentologie et volcanisme du bassin paléozoi͏̈que inférieur de Kiffa et sa structuration varisque (Mauritanie, Mali)." Aix-Marseille 3, 1996. http://www.theses.fr/1996AIX30118.
Повний текст джерелаАнотація:
Cette thèse met en évidence deux phases extensionnelles au Paléozoi͏̈que de la marge ouest africaine qui ont précédé l'orogenèse varisque du Carbonifère sup. Au Permien inf. La première phase d'âge Cambrien probable, concerne le bassin de Kiffa alors que la seconde phase résulte du petit résulte du petit bassin océanique d'Hamdallaye daté du Dévonien moyen, autour de 380 Ma, par la méthode 40Ar/39Ar (roche totale de pillow basalte de type T-MORB). Le bassin paléozoi͏̈que inf. De Kiffa comprend trois groupes discordants. Ce sont, de haut en bas, a) le groupe cambro-ordovicien de N'Diéo, composé de grès alluviaux en tresses et localement turbidique, b) celui de N'Douméli, représenté par des carbonates et grès intertidaux, et c) le groupe cambrien de Nagara qui repose en discordance sur le craton ouest-africain et le groupe Protérozoi͏̈que terminal de Bakoye. Le groupe de Nagara est une formation post-glaciaire varangienne constituée de roches volcaniques "acides" (rhyolite aphyrique, ignimbrite et jaspe), et de sédiments volcanodétritiques et ferrugineux. Le bassin de Kiffa au Cambrien est caractérisé par une alimentation multi-sources et par la faille normale de Massar qui est l'une des principales sources volcaniques "acides" du bassin. Deux types de resédimentation sont proposés pour ce bassin d'arrière-arc : submarine fan dans le compartiment oriental où est conservé un delta ignimbritique progradant vers le continent ouest-africain, et slope-apron dans le compartiment occidental où se développaient des rampes sous-marines générées par une paléosismicité discrète qui s'affirme dans les BIF. Les apports du continent ouest-africain sont distingués des produits calco-alcalins venant probablement d'un arc volcanique fonctionnant depuis le Protérozoi͏̈que terminal l'ouest de la faille de Massar. Les groupes cambro-ordoviciens du bassin de Kiffa, en onlaps successifs sur le groupe de Nagara, illustrent la fin de la phase extensionnelle d'arrière-arc. La sédimentation intertidale (base du groupe de N'Douméli) puis de plaine d'inondation d'un réseau fluviatile anastamosé (base du groupe de N'Diéo) enregistre le basculement progressif vers le Nord de la marge ouest-africaine amincie. La structuration varisque des deux bassins est un gradient d'amortissement d'Ouest en Est de la chaîne des Mauritanides, et de déformations de très basses températures. .This thesis presents evidence for two major phases of Paleozoic extension of the West African Margin after its Panafrican structuration, that are followed by the Variscan orogeny in the Late Carboniferous to Early Permian. The first phase of Cambrian age gave rise to the Kiffa Basin, whereas the second resulted in the establishment of the small oceanic basin of Hamdallaye in which T-MORB's evolved, that yielded a 382 ± 4 Ma (middle Devonian) 40Ar/39Ar whole rock age. The Kiffa Basin comprises three Lower Paleozoic sedimentary sequences separated by unconformities. The oldest lithologic unit, the Nagara Group, is characterised by, amongst others, ash and rhyolitic flows that crop out along the Massar Fault. To the East of this extensional fault deposition occurred in a deltaic environment in which pyroclastic submarine flows succeeded subaqueous debris flows. To the West, however, deeper fades evolved with reworked marine and slope-apron sediments of various sources; typically rocks in BIF facies show indications for soft-deformation. The rocks of the Nagara Group are interpreted as deposited in a back-arc basin. The subsequent series of the N'Doumeli Group, comprising carbonates and intertidal sandstones, are deposited independantly of the two crustal blocks separated by the Massar Fault, marking the end of the Cambrian extensional back-arc setting. Cambro-Ordovician rocks of the Kiffa Basin, the, locally turbiditic, braided river sandstones of the N'Diéo Group, indicate a tilting of the margin to the North. Both Paleozoic basins have been inverted and deformed during the Variscan orogeny, the intensity of which decreased to the East. The Hamdallaye Basin has been overthrust by the internal zones of the meridional Mauritanide belt, the very-low-grade metamorphism associated with the event has been dated by the 40Ar/39Ar method at about 310 My. The Variscan deformation of the series of the Kiffa Basin has yielded strongly dysharmonic folds, but metamorphism did not take place. The inverted Massar Fault forms the eastern Variscan Front of the meridional Mauritanide belt. The eastern Variscan Front is covered by the non-deformed red beds of the Galla Guind6 Group that are probably of Permo-Triassic age and the major Variscan Front is cut by presumably late to post variscan normal faults
16
Gilet, Johan. "Dérégulations neuro-développementales impliquées dans les malformations du développement cortical associées aux mutations du gène KIF2A : apport d'un modèle murin knock-in conditionnel." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ104.
Повний текст джерелаАнотація:
A l’aide d’études génétiques, notre équipe, a identifié chez des patients avec des malformations du développement cortical (MDC), des mutations dans le gène KIF2A, une kinésine impliquée dans la dynamique des microtubules. Afin d’étudier dans un contexte physiologique l’impact de ces mutations sur le développement cortical, nous avons développé un modèle murin exprimant la mutation p.His321Asp de KIF2A. Les analyses neuro-anatomiques et neuro-développementales des souris exprimant la mutation ont permis de mettre en évidence une microcéphalie, et des anomalies de positionnement neuronale dans le cortex et l’hippocampe. Les explorations phénotypiques, nous ont permis de montrer une susceptibilité accrue à l’épilepsie chez la souris mutante. De plus, des analyses fonctionnelles sur les fibroblastes de patient et par purification de la protéine mutante ont montré l’incapacité de la protéine mutante à dépolymériser les microtubules. Nous pensons que l’ensemble des résultats obtenus lors de ce projet de thèse pourra apporter une meilleure compréhension des mécanismes physiopathologiques impliqués dans les MDC lié aux mutations dans KIF2ABy using genetic studies, our team have identified in patient with malformations of cortical development, missense mutations in the KIF2A gene, a kinesin involved in microtubules depolymerization. In order to study in a physiological context the impact of these mutations on the cortical development, we have developed expressing the KIF2A p.His321Asp mutation. The first neuro-anatomical and neuro-developmental analyzes of the mice expressing the mutation during embryonic development allowed us to highlight microcephaly and neuronal positioning abnormalities in the cortex and the hippocampus. Phenotypic explorations allowed us to highlight increased susceptibility to epilepsy in the mutant mouse. In addition, functional analyzes using patient fibroblasts and purification of the mutant protein have shown that the mutant protein can not depolymerize microtubules. We believe that all the results obtained during this thesis project will provide a better understanding of the pathophysiologic mechanisms involved in malformations of cortical development related to mutations in the KIF2A gene
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Lee, Han Kyu Verfasser], and Matthias [Akademischer Betreuer] [Kneussel. "Analysis of the adaptor proteins, gephyrin and GRIP1, in KIF5-driven neuronal transport in Mus musculus, (Linnaeus, 1758) / Han Kyu Lee. Betreuer: Matthias Kneussel." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2011. http://d-nb.info/1020458259/34.
Повний текст джерела
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Chen, Feng-Tian. "Transport de l'enzyme lysosomale alpha-L-iduronidase dans les prolongements neuronaux." Paris 7, 2005. http://www.theses.fr/2005PA077178.
Повний текст джерела
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Correia, Patrícia Maria Dias. "Identification and characterization of potential therapeutic targets for spinal cord repair." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22055.
Повний текст джерелаАнотація:
Mestrado em Biomedicina MolecularTraumatic spinal cord injury (SCI) is a devastating event that leads to loss of neurological functions below the vertebral level of the lesion. As adult neurons from central nervous system (CNS) fail to regenerate when injured, the consequences of SCI are partially or totally irreversible. The lack of regeneration ability of CNS neurons has been studied for years but still no effective treatment was found for this pathology; only steroids are validated and recognized as a pharmacologic treatment attempt, but just limit the lesion extent. This work focused on finding putative candidate genes involved in regeneration that could be targeted for therapy. A bioinformatics analysis based on studies with rodent SCI models, where a regenerative treatment attempt was applied and functional recovery was observed, was performed and some common regulated genes were found in the analysed studies. KIF4A and MPP3 genes were highlighted for further experimental studies in a regenerative model: a rodent model of peripheral nervous system (PNS) injury, with crush or transection of the sciatic nerve. Our results demonstrated that KIF4A and MPP3 are expressed and regulated in the lesioned sciatic nerve and in the corresponding dorsal root ganglia (DRG). Moreover, these genes also showed protein distribution in spinal cord tissue sections, in sciatic nerve and in DRG cuts, revealing that they are neuronal specific. These results represent important remarks to instigate further studies regarding the role of these genes in regenerative processes of lesioned neuronal tissues and the possibility of becoming important therapeutic targets in spinal cord injuries or related pathologies affecting the spinal cord integrity
A lesão traumática da medula espinal é um evento devastador que leva à perda de funções neurológicas abaixo do nível vertebral da lesão. Devido à falta de capacidade regenerativa dos neurónios adultos do sistema nervoso central, quando lesionados, as consequências das lesões são parcial ou totalmente irreversíveis. A falta de capacidade de regeneração dos neurónios do SNC tem sido estudada há anos, mas ainda não foi encontrado um tratamento efetivo para esta patologia; apenas os esteroides são validados e reconhecidos como um tratamento farmacológico, mas só limitam a extensão da lesão. Este trabalho centrou-se na procura de genes hipoteticamente envolvidos em regeneração do sistema nervoso, que possam ser candidatos a alvos de terapia para lesões na medula. Foi realizada uma análise bioinformática baseada em estudos com modelos de roedores com lesão da medula espinal, onde uma tentativa de tratamento regenerativo foi aplicada e observou-se recuperação funcional, e foram levantados os genes regulados comuns aos três estudos. Os genes KIF4A e MPP3 foram destacados para estudos experimentais adicionais num modelo regenerativo: um modelo de roedor, de lesão do sistema nervoso periférico, com esmagamento ou corte do nervo ciático. Os resultados demonstraram que os genes KIF4A e MPP3 são expressos e regulados no nervo ciático lesionado e nos gânglios da raiz dorsal correspondentes. Além disso, estes genes também mostraram distribuição proteica em secções de tecido de medula espinhal, de nervo ciático e em cortes de DRG, desvendando que possam ser específicos de tecido neuronal. Estes resultados representam observações importantes para instigar estudos adicionais sobre o papel destes genes nos processos regenerativos de tecidos neuronais lesionados e a possibilidade de se tornarem alvos terapêuticos importantes para lesões ou patologias relacionadas que afetem a integridade da medula espinal.
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Cavallin, Mara. "Physiopathologie moléculaire et cellulaire des anomalies du développement du cortex cérébral : le syndrome d'Aicardi WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells TLE1, a key player in neurogenesis, a new candidate gene for autosomal recessive postnatal microcephaly Mutations in TBR1 gene leads to cortical malformations and intellectual disability Aicardi syndrome: Exome, genome and RNA-sequencing of a large cohort of 19 patients failed to detect the genetic cause Recurrent RTTN mutation leading to severe microcephaly, polymicrogyria and growth restriction Recurrent KIF2A mutations are responsible for classic lissencephaly Recurrent KIF5C mutation leading to frontal pachygyria without microcephaly Rare ACTG1 variants in fetal microlissencephaly De novo TUBB2B mutation causes fetal akinesia deformation sequence with microlissencephaly: An unusual presentation of tubulinopathy A novel recurrent LIS1 splice site mutation in classic lissencephaly Further refinement of COL4A1 and COL4A2 related cortical malformations Prenatal and postnatal presentations of corpus callosum agenesis with polymicrogyria caused By EGP5 mutation Delineating FOXG1 syndrome from congenital microcephaly to hyperkinetic encephalopathy Delineating FOXG1 syndrome: From congenital microcephaly to hyperkinetic encephalopathy." Thesis, Sorbonne Paris Cité, 2019. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2213&f=18201.
Повний текст джерелаАнотація:
Les malformations du cortex cérébral (MDC) représentent une cause importante de handicap et d'épilepsie pharmaco-résistante. Le séquençage à haut débit a permis une amélioration considérable de l'identification des bases moléculaires des MDC non syndromiques. Toutefois, certaines formes, notamment les MDC complexes, demeurent inexpliquées. Mon projet de thèse a pour objectif de progresser dans la compréhension des MDC complexes en utilisant deux modèles : les microlissencéphalies (MLIS) et le syndrome d'Aicardi (AIC), une forme syndromique particulière associant des malformations de l'oeil et du cerveau uniquement rapporté chez les filles. L'étude par séquençage d'exome en trios de 16 familles MLIS m'a permis d'identifier et de caractériser un nouveau gène, WDR81, impliqué dans le cycle cellulaire. Par la même stratégie, j'ai pu identifier un variant homozygote pathogène dans TLE1, un partenaire majeur de FOXG1 dans la balance prolifération/différenciation de progéniteurs neuronaux, dans une famille consanguine de microcéphalie postnatale dont le phénotype est proche du syndrome FOXG1. En parallèle, mes travaux ont permis de préciser les spectres phénotypiques associés à RTTN, EPG5, COL4A1, COL4A2, TBR1, KIF5C, KIF2A et FOXG1. La deuxième partie de mon projet avait pour objet l'identification des bases moléculaires du syndrome d'Aicardi à partir d'une cohorte internationale de 19 patientes. Après avoir exclu un biais d'inactivation du chromosome X et la présence de microremaniements chromosomiques, j'ai réalisé un séquençage d'exome en trio. Aucun variant récurrent n'a été retrouvé dans les séquences codantes. Dans un second temps, j'ai testé une approche combinant les données du séquençage de génome et l'analyse du transcriptome (RNA-Seq) sur fibroblastes, me permettant d'identifier des transcrits dérégulés qui étaient impliqués dans le développement du cerveau et de l'oeil. J'ai comparé les résultats de cette analyse avec ceux de l'analyse du génome dans le but d'identifier des variants dans ces gènes candidats. En conclusion, mon travail de thèse a permis d'améliorer la connaissance des bases moléculaires des MDC complexes et d'ouvrir des perspectives de nouveaux mécanismes tels que ceux engageant les gènes WDR81 et EPG5, et le rôle des endosomes et de l'autophagie dans les MDC, et aussi TLE1 comme nouvelle cause de microcéphalies postnatales. Mes travaux ont également permis de générer une collection de données de séquençage haut débit (WES, WGS et RNA-Seq) qui seront mises en commun dans le cadre d'un consortium international afin de développer des nouvelles stratégies d'analyse en particulier pour les séquences non codantes. Cette approche permettra également d'ouvrir la voie vers la compréhension des mécanismes cellulaires impliqués dans la formation du cerveau et de l' œilMalformations of cortical development (MCD) are a major cause of intellectual disability and drug-resistant epilepsy. Next Generation Sequencing (NGS) has considerably improved the identification of the molecular basis of non-syndromic MCD. However, certain forms, including complex MCD, remain unexplained. My PhD project aimed to improve the understanding of complex MCD using two disorders: Microlissencephaly (MLIS) and Aicardi Syndrome (AIC), the latter associating brain and eye malformations and only reported in girls. Trio Whole Exome Sequencing (WES) performed in 16 MLIS families allowed me to identify and functionally characterize a new MLIS gene, WDR81, in which mutations lead to cell cycle alteration. Moreover, using the same strategy, I was able to identify a pathogenic homozygous variant in TLE1 in a patient from consanguineous family with a postnatal microcephaly, suggestive of a FOXG1-like presentation. Interestingly, TLE1 is a major partner of FOXG1, a gene involved in maintaining the balance between progenitor proliferation and differentiation. In parallel, my work allowed me to redefine the phenotypic spectrum associated with RTTN, EPG5, COL4A1 and COL4A2, TBR1, KIF5C, KIF2A and FOXG1. The second part of my PhD program was aimed at identifying the genetic basis of AIC in an international cohort of 19 patients. After excluding a skewed X chromosome inactivation and the presence of chromosomal rearrangements, I performed WES in trios. The analysis of the data from WES did not allow me to identify any recurrent variants. I therefore tested a new approach combining Whole Genome Sequencing (WGS) and RNA-Sequencing (RNA-Seq) on fibroblast cells. I identified a number of deregulated transcripts implicated in brain and eye development. I compared the results of this analysis with the WGS analysis in order to find variants in these candidate genes. In conclusion, these studies have improved the knowledge of the molecular basis of complex MCD, such as TLE1 in postnatal microcephaly, and revealed the pathogenic mechanisms such as WDR81 in cell cycle progression and EPG5 in endosomes and autophagy. My work has also generated a collection of NGS data (WES, WGS and RNA-Seq) that will be shared in an international consortium to develop new analytical strategies, in particular for the non-coding DNA regions. This novel strategy provides opportunities to improve understanding of the cellular mechanisms involved in brain and eye development
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ARORA, ANKITA. "SCREENING AND DESIGNING OF KIF5A LIKE MOTOR PROTEINS IN AMYOTROPHIC LATERAL SCLEROSIS (ALS)." Thesis, 2019. http://dspace.dtu.ac.in:8080/jspui/handle/repository/16771.
Повний текст джерелаАнотація:
KIF5A a motor neuron protein expressed in neuron is responsible for anterograde transportation of organelles, proteins and RNA. Variation within KIF5A leading to disruption of axonal transport serve as a hallmark for various neurodegenerative diseases such as hereditary spastic paraplegia (HSP10), Charcot-Marie-Tooth disease type 2 (CMT2), amyotrophic lateral sclerosis (ALS). Amyotrophic Lateral Sclerosis (ALS) is one of the incurable motor neuron disorders in which progressive loss of upper and lower motor neuron occur, with the incidence of 1-5 per 100,000. Studies have shown KIF5A is a novel ALS gene, an association of rare KIF5A variant with was predominantly due to a mutation in splice site region which result in loss of function of KIF5A protein involved in vesicular transport in mitochondria, Golgi-ER region. Non-synonymous single nucleotide polymorphism (nsSNPs) has potential to alter structure and function of protein thus it is important to differentiate potential damaging and deleterious nsSNPs from neutral. The aim of our study is analyse the functional effect of non-synonymous single nucleotide polymorphism (nsSNPs) leading to dysfunction of KIF5A protein in axonal transport using bioinformatics tools. In-silico screening of 512 missense SNPs associated with KIF5A predicted 109 nsSNPs to be damaging in nature. Subsequent analysis of these nsSNPs predicted 5 nsSNPs (A268T, R369W, T644M, R712L and P986L) to be highly deleterious among the entire prediction program. The complete KIF5A protein structure was modeled using ab-initio modeling. The study highlighted three possible nsSNPs (T644M, R712L and P986L) to increased stability of mutant protein, thus altering the function of protein. Exact biological mechanism associated with above predicted nsSNPs still needs to validate by invitro studies. Further we designed novel synthetic compounds to inhibit Pro986Leu variant of KIF5A. A compound library was prepared that consisted of natural compounds retrieved from the ZINC database. The prepared library was then screened against this missense variant KIF5A at specific domains which is involved in ALS and then docking was done. This was completely a new approach to target ALS. The results obtained from this study need to be experimentally validated further so that we can prove our computational work and keep working in that direction with the assurance that our approach is right. The study provided a path to explore association of these predicted nsSNPs in disease susceptibility and to design target dependent drugs for therapeutic application.
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Sye, Ko-Wei, and 謝克威. "Study of the physiological role of KIF3A and KIF5B–using PC12 cell as a model system." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/mm67q3.
Повний текст джерелаАнотація:
碩士國立陽明大學
生命科學暨基因體科學研究所
97
Kinesins constitute a superfamily of microtubule-based motor proteins. Some of them regulate polarized transport of organelles and proteins in nerve system to result in differential morphology and functions in subcellular regions of neurons. Because nerve growth factor (NGF) induces na��ve PC12 cells to acquire neuronal-like differential morphology and functions among cell body and neurites. Therefore, KIFs seem to play a role in NGF-mediated differentiation of PC12 cells. This study is to understand whether KIF3 and KIF5, which possibly regulate transport calcium pools and vesicles, involves in the effects of NGF on calcium homeostasis and exocytotic activity of PC12 cells. Overexpression of shKIF5B instead of shKIF3A or DN-KIF3A-EGFP reduced NGF-induced neurite outgrowth. NGF-differentiated PC12 cells overexpressing either EGFP as control, or DN-KIF3A or shKIF5B were stimulated by ATP to evoke [Ca2+]i increase, and changes of [Ca2+]i in cell body and neurites of these cells were visualized by calcium imaging. DN-KIF3A and shKIF3A reduced resting [Ca2+]i in cell bodies and neurites of NGF-differentiated PC12 cells, but difference of resting calcium among cell bodies and neurites is not affected, i.e. higher resting [Ca2+]i in neurite than in cell body. To test whether mitochondria may be re-distributed by DN-KIF3A to affect calcium homeostasis in PC12 cells, subcellular distribution of mitochondria was visualized by DsRed-Mito. There is no significant difference between control and DN-KIF3A-overexpressing cells. Moreover, only TG (thapsigargin, ER calcium pump inhibitor) instead of CCCP (carbonyl cyanide m-chlorophenylhydrazone, inhibitor to deplete mitochondrial calcium pool) reduces differential resting [Ca2+]i among neuritis and cell bodies and the effects of DN-KIF3A on resting [Ca2+]i, and support that KIF3A regulates resting [Ca2+]i is not mediated by mitochondria calcium pools. Such reduction of resting [Ca2+]i by shKIF3A results in decreased LDCVs (Large dense core vesicle) exocytosis. Similar to shKIF3A, shKif5B reduces resting calcium level only in NGF-treated cells instead of na��ve cells, even morphology of NGF-treated and na��ve KIF5B knock down cells are similar. In conclusion, KIF3A and KIF5B play a role in calcium homeostasis only in NGF-treated PC12 cells. But the mechanism in how KIFs regulate calcium homeostasis and exocytosis needs to be further studied.
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jian, shun-yi, and 簡順億. "The kinetic analysis of KIF1A onthe microtubule." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/79953070904453266553.
Повний текст джерелаАнотація:
碩士國立成功大學
工程科學系碩博士班
93
KIF1A is a one-head motor protein that moves along microtubule toward plus end. Like the other molecular motors, KIF1A use ATP hydrolysis and product release to produce movement. In this paper, we construct a model to analyze KIF1A movement, that was built up ATP hydrolyze cycle and motion behavior of KIF1A. The process is including four steps: start, detach, oscillate stochastic, and re-bind. In this model, we use the enzyme kinetics and stochastic processes analysis for computing the mean displacement and standard deviation displacement. Then, we calculate the mean displacement with external force formula. When the external force raise, the mean displacement is decreased. Finally, we adopt Langevin equation to describe the Brownian motion effect and use Forkker-planck equation to calculate probability density for stepping motion. The analysis reveals the variation of probability distribution with standard deviation displacement. The main factor in influencing standard deviation displacement is reaction time.
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Chen, Szu-Ying, and 陳思穎. "Functional characterization of TRAX and it's binding protein, KIF2A." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/19816387760239052295.
Повний текст джерелаАнотація:
碩士國立陽明大學
神經科學研究所
98
腺苷酸第二亞型受體(A2A adenosine receptor; 簡稱A2A R) 分布在腦中許多區域中，特別在紋狀體最為豐富。它具有調控神經可塑性和神經發育的功能。 我們過去的研究發現活化A2A R會透過其 C 端結合蛋白Translin-associated protein X (TRAX) 以回復因阻斷p53所造成神經突觸生長損傷情形。 TRAX除了是A2A R的結合蛋白外、它也會與其他蛋白作結合，例如: Translin 和 KIF2A。 TRAX 是分布很廣的蛋白質，其中以腦和睪丸組織為最多。在各物種上它是一個高度保留的基因，且與染色體轉位作用和細胞增質有關。臨床上研究也顯示TRAX與精神分裂症有高度相關性。且造成大腦前額葉灰質區域減少，及記憶喪失的現象。為了瞭解TRAX在生物體上所扮演的功能，我們利用gene trap 的技術發展出TRAX-null小鼠的世代。利用西方墨點法和免疫組織化學法證明其動物在各組織沒有表現TRAX。且有近似10-20% 胚胎死亡的現象發生在heterozygous及 homozygous 的TRAX-null 小鼠。 且在生存的null小鼠中，至20個月大時有體重降低的現象發生。利用免疫組織化學法中，使用. anti-calbindin的抗體顯示TRAX null小鼠小腦的Purkinje neuron 細胞型態發生異常。且在微陣列晶片技術及及時定量PCR分析顯示在海馬迴組織的有許多基因表現異常情形。也發現TRAX null小鼠展現出許多不正常的行為可能與海馬迴和小腦的功能有相關性。所得到的結果將提供TRAX在腦組織中所扮演重要的角色。
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Hou, Jen-Tzu, and 侯恁慈. "Ectopic ATP Synthase trafficking via KIF5B and Drp1 interaction." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/75hyss.
Повний текст джерелаАнотація:
碩士國立臺灣大學
分子與細胞生物學研究所
106
Adenosine triphosphate (ATP) synthase, an inner membrane enzyme of mitochondria, is essential for ATP production in many cell biological processes. Our previous studies have shown that ATP synthases not only existed on mitochondrial inner membrane but also plasma membrane (ectopic ATP synthases) in several cancer cell lines. However, the trafficking mechanism of ATP synthase to cell surface is still required further investigation. According to our previous gene set enrichment analysis (GSEA) results, we inferred ectopic ATP synthases transported to cell surface through the microtubule-mediated mitochondria trafficking. To examine whether this presumption is correct, we conducted flow cytometry and immunocytochemistry (ICC) after treating nocodazole, a microtubule-depolymerizing agent, in cancer cells. The results revealed that microtubule disruption reduced ectopic ATP synthase expression level. In addition, silencing kinesin family member 5B (KIF5B), a microtubule motor protein, with small interfering RNA showed the similar trend with the results of microtubule disruption. On the other hand, we also found that mitochondria dynamic related to ectopic ATP synthase expression. Both flow cytometry and ICC demonstrated that mitochondrial fission protein, dynamic-related protein 1 (Drp1), knockdown and overexpression resulted in low and high ectopic ATP synthase expression respectively. In addition, Drp1 C-terminus was showed more significant than N-terminus in ectopic ATP synthase expression in overexpression experiments. Moreover, we used protein-protein interaction database and docking web server to predict whether KIF5B bound with Drp1 directly. Taken together, these findings suggest that KIF5B-Drp1 complex-mediated mitochondrial trafficking via microtubule may play a crucial role in ectopic ATP synthases transport.
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Boyle, Lia. "A Precision Medicine Approach to Understanding KIF1A Associated Neurological Disorder." Thesis, 2021. https://doi.org/10.7916/d8-0nef-s787.
Повний текст джерелаАнотація:
The functional compartmentalization underlying neuronal polarity makes tightly regulated intracellular transport between the cell body, axons, and dendrites essential for proper development and homeostatic maintenance. Disruptions to neuronal trafficking are a major cause of neurodegenerative disease. Pathogenic variants in the microtubule motor protein KIF1A cause KIF1A Associated Neurological Disorder (KAND), a spectrum of rare neurodegenerative conditions. KAND is clinically and genetically heterogeneous, with a broad phenotypic spectrum and over a hundred pathogenic variants identified. KAND is poorly understood at both the clinical and molecular level, and there is currently no treatment.
This work characterizes the natural history of KAND and describes a novel heuristic severity score. This severity score is then used to show how the location of pathogenic missense variants within the KIF1A motor domain correlates with disease severity, providing evidence the clinical phenotypic heterogeneity in KAND reflects and parallels the molecular phenotypes. Insights from the neuropathology of deceased KAND patients is used to focus a histopathologic assessment of the C3-Kif1aLgdg mouse model. C3-Kif1aLgdg/Lgdg mice have a cerebellar axonal torpedo phenotype, paralleling some of the pathological changes seen in the patients. Phenotypically, the C3-Kif1aLgdg mice were found to recapitulate some of the symptoms seen in patients including progressive spasticity and gait abnormalities associated with hind limb paralysis.
To model the disease at a cellular level, iPSCs were derived from affected individuals and successfully used to generate neural stem cells and neurons. These patient-derived neurons were found to have increased markers of protein aggregates, a cellular phenotype that can be used to test potential treatments. Taken together, these studies provide foundational knowledge for future therapeutic development.
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Chen, Jia-Long, and 陳嘉隆. "Gli2 rescues delays in brain development induced by Kif3a dysfunction." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/x88khb.
Повний текст джерелаАнотація:
博士國立陽明大學
腦科學研究所
106
The primary cilium in neural stem cells plays distinct roles in different stages during cortical development. Ciliary dysfunctions in human (i.e., ciliopathy) cause developmental defects in multiple organs, including brain developmental delays, which lead to intellectual disabilities and cognitive deficits. However, effective treatment to this devastating developmental disorder is still lacking. Here we first investigated the effects of ciliopathy on neural stem cells by knocking down Kif3a, a kinesin II motor required for ciliogenesis, in the neurogenic stage of cortical development by in utero electroporation of mouse embryos. Brains electroporated with Kif3a shRNA showed defects in neuronal migration and differentiation, delays in neural stem cell cycle progression, and failures in interkinetic nuclear migration. Interestingly, introduction of Gli1 and Gli2 both can restore the cell cycle progression by elevating cyclin D1 in neural stem cells. Remarkably, enforced Gli2 expression, but not Gli1, partially restored the ability of Kif3a-knockdown neurons to differentiate and move from the germinal ventricular zone (VZ) to the cortical plate. Moreover, Cyclin D1 knockdown abolished Gli2’s rescue effect. These findings suggest Gli2 may rescue neural stem cell proliferation, differentiation and migration through Cyclin D1 pathway and may serve as a potential therapeutic target for human ciliopathy syndromes through modulating the progression of neural stem cell cycle.
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Schäfer, Barbara [Verfasser]. "KIF5C, ein neuer Bindungspartner für die Proteinkinase CK2 / vorgelegt von Barbara Schäfer." 2008. http://d-nb.info/996155791/34.
Повний текст джерела
29
Hu, Daniel Jun-Kit. "Roles for Cytoplasmic Dynein and the Unconventional Kinesin, KIF1a, during Cortical Development." Thesis, 2015. https://doi.org/10.7916/D8Z89BG9.
Повний текст джерелаАнотація:
Radial glial progenitor (RGP) cells are neural stem cells that give rise to the majority of neurons, glia, and adult stem cells during cortical development. These cells divide either symmetrically to form two daughter RGP cells or asymmetrically to form a daughter RGP cell or a daughter neuron/neuronal precursor. In between divisions, the nuclei of RGP cells oscillate in coordination with the cell cycle in a form of behavior known as interkinetic nuclear migration (INM). RGP nuclei migrate basally during G1, undergo S phase, and migrate apically during G2 to the apical, ventricular surface (VS). Mitosis only occurs when the nucleus reaches the VS. Two microtubule-associated motor proteins are required to drive nuclear movement: the unconventional kinesin, Kif1a, during G1-specific basal migration and cytoplasmic dynein during G2-specific apical migration. The strict coordination of motor activity, migratory direction, and cell cycle phase is highly regulated and we find that a G2 cell cycle-dependent protein kinase activates two distinct G2-specific mechanisms to recruit dynein to nuclear pores. The activities of these pathways initiate apical nuclear migration and maintain nuclear movement throughout G2.
Originally identified in HeLa cells, we find the two G2-specific recruitment pathways (“RanBP2-BicD2” and “Nup133-CENP-F”) are conserved in RGP cells. Disrupting either pathway arrests apical nuclear migration but does not affect G1-dependent basal migration. The “RanBP2-BicD2” pathway initiates early during G2 and is maintained throughout the cell cycle phase while the “Nup133-CENP-F” pathway is activated later in G2. Forced targeting of dynein to the nuclear envelope (NE) restores apical nuclear migration, with nuclei successfully reaching the VS. We also find that the G2/M-specific Cdk1 serves as a master regulator of apical nuclear migration in RGP cells. Pharmacological drug inhibitors of Cdk1 arrest apical migration without any effect on G1-dependent basal migration. Conversely, overactivating Cdk1 causes premature, accelerated apical nuclear migration. Specifically, Cdk1 drives apical nuclear migration through activation of both the “RanBP2-BicD2” and “Nup133-CENP-F” pathways. Cdk1 acts by phosphorylating RanBP2, priming it for BicD2 interaction. Forced targeting of BicD2-dynein to the NE in a RanBP2-independent manner rescues apical nuclear migration in the presence of Cdk1 drug inhibition. Additionally, Cdk1 seems to activate the “Nup133-CENP-F” at the CENP-F level, phosphorylating the protein to trigger nuclear export.
INM plays an important role in proper cell cycle progression and we find that arresting nuclei away from the VS prevents mitotic entry, demonstrating that apical nuclear migration to the VS is not just a correlated with cell cycle progression, but is required. When apical migration is restored by forced recruitment of dynein to the NE, mitotic entry is restored as well. In contrast, we find that arresting basal migration by Kif1a does not have a major influence on cell cycle progression. RGP cells still enter S-phase despite remaining close to the VS, revealing that, unlike mitotic entry, S-phase entry is not coupled with nuclear positioning. However, symmetric, proliferative divisions are favored over asymmetric, neurogenic divisions after inhibition of basal migration.
We further find that Kif1a and the proteins involved in the two recruitment pathways play additional role later in brain development. After a neurogenic division, the newly-born neuron migrates past the RPG nuclei and they undergo a multipolar morphology. After at least twenty-four hours, the immature neuron then transitions to a bipolar, migratory morphology where it continues migrating towards its final destination along RGP fibers to the cortical plate. We demonstrate that Kif1a and NE dynein recruitment proteins seem to be involved in the multipolar to bipolar transition and RNAi for these proteins prevent further migration by arresting the immature neurons in a multipolar morphology. Kif1a RNAi, in particular, also induced comparable arrest in surrounding control neurons. Further analysis reveal that the multipolar arrest in neurons is independent of the basal nuclear migration arrest in RGP cells. These results identify the control mechanism for NE dynein recruitment in RGP cells to drive apical nuclear migration, the relationship of cell cycle phase progression with nuclear positioning, and the sequential, independent roles of these proteins, particularly Kif1a, in neuronal maturation.
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O'Rourke, ME. "Conditionally and acutely ablating Kif3a from oligodendrocyte progenitor cells impairs primary cilum assembly and cell function." Thesis, 2018. https://eprints.utas.edu.au/30184/1/O_Rourke_whole_thesis.pdf.
Повний текст джерелаАнотація:
The primary cilium is a cellular organelle that can regulate the behaviour of many mitotic progenitor cells, and even some post mitotic cell types. Oligodendrocyte progenitor cells (OPCs) express genes associated with primary cilia assembly, disassembly and signalling. However, whether OPCs have primary cilia assembled on their surface and are functionally influenced by signalling at this organelle is unknown. In this thesis, I show that OPCs are ciliated, both in vitro and in vivo, while mature oligodendrocytes are not. Furthermore, OPCs disassemble and reassemble their primary cilia as they progress through the cell cycle, and this organelle is a critical regulator of OPC proliferation and oligodendrogenesis in adulthood.
In order to examine the importance of the primary cilium for OPC function, the kinesin family member 3a (Kif3a) gene, critical for cilium assembly, was deleted from OPCs in vitro. Kif3adeletion significantly reduced the number of OPCs with assembled primary cilia on their surface and decreased OPC proliferation (Chapter 3). As Pdgfrα-CreER\(^{T2}\) transgenic mice target DNA recombination to OPCs, without significantly affecting PDGFRα\(^+\) cells in other tissues and organs (including the kidney, spleen, liver, intestine, heart, gastrocnemius, sciatic nerve, pituitary gland and adrenal gland) (Chapter 4), these mice were selected to conditionally delete Kif3a from OPCs, to examine the importance of this organelle in vivo (Chapter 5). Consistent with the in vitro findings, Kif3a-deletion from OPCs reduced the number of OPCs that had assembled primary cilia on their surface in the corpus callosum (CC) and reduced proliferation by ~30% in the CC and ~50% in the motor cortex. While Kif3a-deleation had no effect on OPC density, it halved the number of new oligodendrocytes produced in both the CC and the motor cortex. As the reduced proliferation rate of Kif3adeleted OPCs does not account for the substantial decrease in new oligodendrocyte number, these data indicate that the primary cilium also promotes oligodendrocyte differentiation and / or new oligodendrocyte survival in the brain.
Genetically ablating OPCs, disrupting OPC function and preventing oligodendrogenesis can have behavioural consequences ranging from increased anxiety and depressive behaviours to reduced motor performance and impaired motor learning. However, when oligodendrogenesis was reduced in the CC and motor cortex over a 6-week period, by the conditional deletion of Kif3a from OPCs in vivo, no such behavioural phenotype was observed. These data indicate that deleting Kif3a from OPCs in the adult central nervous system (CNS), which does not remove OPCs from the brain, and only moderately reduces oligodendrogenesis, is not sufficient, at least in the short-term, to have overt behavioural consequences. However, these experiments also pose interesting questions about the function of OPCs, and whether oligodendrogenesis is their only role in the mature CNS.
Overall this research demonstrates that primary cilia are present on the surface of OPCs but absent from mature, myelinating oligodendrocytes and that preventing cilium assembly reduces both OPC proliferation and oligodendrogenesis. I also determined that preventing cilium assembly and reducing oligodendrogenesis did not affect normal CNS function by 7 weeks post gene-deletion.
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Schmidt, Michael. "Regulation of recycling endosomal membrane traffic by a γ-BAR/ kinesin KIF5 complex". Doctoral thesis, 2007. http://hdl.handle.net/11858/00-1735-0000-0006-B375-8.
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Röhlk, Christian [Verfasser]. "Characterization of conventional kinesins Kif3 and Kif5 from Dictyostelium discoideum / vorgelegt von Christian Röhlk." 2007. http://d-nb.info/985849983/34.
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Yen, Ying-Cheng, and 閻映丞. "The role of dynein and dynactin in synaptic vesicle transport and axonal KIF1A/UNC-104 clustering and motility." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/78185799287314415135.
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Tien, Nai-Wen, та 田乃文. "類Tau蛋白PTL-1被KIF1A/UNC-104運輸並調控其運輸特性". Thesis, 2010. http://ndltd.ncl.edu.tw/handle/66147001724400610398.
Повний текст джерелаАнотація:
碩士國立清華大學
分子與細胞生物研究所
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Tauopathies include a broad range of neuropathological disorders that are based on defects in tau metabolisms. The microtubule-binding protein tau plays roles in Alzheimer’s disease in which tau accumulates in neurofibrillary tangles. In general, cargo accumulation (amyloid precursor protein, tau, neurofilaments) is a common observed phenomenon in degenerated neurons and it has been found that elevation of tau expression disrupts cargo transport, leading to cargo accumulation. Thus it seems to be important to investigate the interaction between microtubule-associated proteins and molecular motors. Here, we set out to investigate the interaction of tau/PTL-1 (Protein with Tau-Like repeats) and the major axonal transporter KIF1A/UNC-104 in Caenorhabditis elegans. In PTL-1 knock-out worms, the motility of UNC-104 is critically affected: more motor reversals for retrograde movements are observed and at the same time more pausing events for retrograde movements can be seen (compared to wildtype). Interestingly, similar behavior can be observed for UNC-104’s major cargo synaptobrevin-1 alone. Moreover, UNC-104 and PTL-1 co-localize and even co-migrate in the nervous system of living animals, suggesting that PTL-1 might be a cargo of UNC-104. Further motility analysis shows comparable fast transport rate of PTL-1. Last, we used bimolecular fluorescence complementation assay (BiFC) to test for interactions between PTL-1 and UNC-104 in the living worms. Indeed, using this novel assay (that can effortlessly replace the more complicated FLIM/FRET assay) we were able to identify interactions between these two proteins.
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Schmidt, Michael [Verfasser]. "Regulation of recycling endosomal membrane traffic by a γ-BAR [gamma-BAR], kinesin KIF5 complex / submitted by Michael Schmidt". 2008. http://d-nb.info/988980355/34.
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Nedvědová, Jana. "Popis interakcí mezi histondeacetylasou 6 a kinesinem." Master's thesis, 2019. http://www.nusl.cz/ntk/nusl-397037.
Повний текст джерелаАнотація:
Intracellular transport is provided by two major types of molecular motors kinesins and cytoplasmic dynein. Kinesin-1 is a molecular motor that transports molecules and organelles along microtubule tracks anterogradely. Specific protein-protein interactions are required to activate kinesin-1 as the free kinesin exist in an autoinhibited state. The activation of kinesin-1 induces its conformational change, enables microtubule binding and ATP hydrolysis necessary for the directional cargo transport. HDAC6 is a multifunctional protein composed of several domains. It plays an important role in many microtubule dependent processes as HDAC6 is a major tubulin deacetylase. It has been shown that HDAC6 manipulation (inhibition/genetic ablation) affects transport along microtubules but the exact mechanisms are unknown. The effect can be caused either by deacetylation microtubules or direct interaction with molecular motors. This thesis is focused on characterization of interactions between kinesin-1 and HDAC6 that have not been described so far. To this end, we expressed and purified various constructs of kinesin-1 and HDAC6 and tested their interactions by microscale thermophoresis (MST) and hydrogen deuterium exchange (HDX) to determine affinity and interaction sites, respectively. MST data revealed that...