Добірка наукової літератури з теми "C9ORF72 complex"
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Статті в журналах з теми "C9ORF72 complex":
1
Tang, Dan, Jingwen Sheng, Liangting Xu, Xiechao Zhan, Jiaming Liu, Hui Jiang, Xiaoling Shu, et al. "Cryo-EM structure of C9ORF72–SMCR8–WDR41 reveals the role as a GAP for Rab8a and Rab11a." Proceedings of the National Academy of Sciences 117, no. 18 (April 17, 2020): 9876–83. http://dx.doi.org/10.1073/pnas.2002110117.
Анотація:
A massive intronic hexanucleotide repeat (GGGGCC) expansion in C9ORF72 is a genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, C9ORF72, together with SMCR8 and WDR41, has been shown to regulate autophagy and function as Rab GEF. However, the precise function of C9ORF72 remains unclear. Here, we report the cryogenic electron microscopy (cryo-EM) structure of the human C9ORF72–SMCR8–WDR41 complex at a resolution of 3.2 Å. The structure reveals the dimeric assembly of a heterotrimer of C9ORF72–SMCR8–WDR41. Notably, the C-terminal tail of C9ORF72 and the DENN domain of SMCR8 play critical roles in the dimerization of the two protomers of the C9ORF72–SMCR8–WDR41 complex. In the protomer, C9ORF72 and WDR41 are joined by SMCR8 without direct interaction. WDR41 binds to the DENN domain of SMCR8 by the C-terminal helix. Interestingly, the prominent structural feature of C9ORF72–SMCR8 resembles that of the FLNC–FNIP2 complex, the GTPase activating protein (GAP) of RagC/D. Structural comparison and sequence alignment revealed that Arg147 of SMCR8 is conserved and corresponds to the arginine finger of FLCN, and biochemical analysis indicated that the Arg147 of SMCR8 is critical to the stimulatory effect of the C9ORF72–SMCR8 complex on Rab8a and Rab11a. Our study not only illustrates the basis of C9ORF72–SMCR8–WDR41 complex assembly but also reveals the GAP activity of the C9ORF72–SMCR8 complex.
2
Nörpel, Julia, Simone Cavadini, Andreas D. Schenk, Alexandra Graff-Meyer, Daniel Hess, Jan Seebacher, Jeffrey A. Chao, and Varun Bhaskar. "Structure of the human C9orf72-SMCR8 complex reveals a multivalent protein interaction architecture." PLOS Biology 19, no. 7 (July 23, 2021): e3001344. http://dx.doi.org/10.1371/journal.pbio.3001344.
Анотація:
A major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum disorder is the hexanucleotide G4C2 repeat expansion in the first intron of the C9orf72 gene. Many underlying mechanisms lead to manifestation of disease that include toxic gain-of-function by repeat G4C2 RNAs, dipeptide repeat proteins, and a reduction of the C9orf72 gene product. The C9orf72 protein interacts with SMCR8 and WDR41 to form a trimeric complex and regulates multiple cellular pathways including autophagy. Here, we report the structure of the C9orf72-SMCR8 complex at 3.8 Å resolution using single-particle cryo-electron microscopy (cryo-EM). The structure reveals 2 distinct dimerization interfaces between C9orf72 and SMCR8 that involves an extensive network of interactions. Homology between C9orf72-SMCR8 and Folliculin-Folliculin Interacting Protein 2 (FLCN-FNIP2), a GTPase activating protein (GAP) complex, enabled identification of a key residue within the active site of SMCR8. Further structural analysis suggested that a coiled-coil region within the uDenn domain of SMCR8 could act as an interaction platform for other coiled-coil proteins, and its deletion reduced the interaction of the C9orf72-SMCR8 complex with FIP200 upon starvation. In summary, this study contributes toward our understanding of the biological function of the C9orf72-SMCR8 complex.
3
Yang, Mei, Chen Liang, Kunchithapadam Swaminathan, Stephanie Herrlinger, Fan Lai, Ramin Shiekhattar, and Jian-Fu Chen. "A C9ORF72/SMCR8-containing complex regulates ULK1 and plays a dual role in autophagy." Science Advances 2, no. 9 (September 2016): e1601167. http://dx.doi.org/10.1126/sciadv.1601167.
Анотація:
The intronic GGGGCC hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) is a prevalent genetic abnormality identified in both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Smith-Magenis syndrome chromosomal region candidate gene 8 (SMCR8) is a protein with unclear functions. We report that C9ORF72 is a component of a multiprotein complex containing SMCR8, WDR41, and ATG101 (an important regulator of autophagy). The C9ORF72 complex displays guanosine triphosphatase (GTPase) activity and acts as a guanosine diphosphate–guanosine 5′-triphosphate (GDP-GTP) exchange factor (GEF) for RAB39B. We created Smcr8 knockout mice and found that Smcr8 mutant cells exhibit impaired autophagy induction, which is similarly observed in C9orf72 knockdown cells. Mechanistically, SMCR8/C9ORF72 interacts with the key autophagy initiation ULK1 complex and regulates expression and activity of ULK1. The complex has an additional role in regulating later stages of autophagy. Whereas autophagic flux is enhanced in C9orf72 knockdown cells, depletion of Smcr8 results in a reduced flux with an abnormal expression of lysosomal enzymes. Thus, C9ORF72 and SMCR8 have similar functions in modulating autophagy induction by regulating ULK1 and play distinct roles in regulating autophagic flux.
4
Amick, Joseph, Arun Kumar Tharkeshwar, Catherine Amaya,, and Shawn M. Ferguson. "WDR41 supports lysosomal response to changes in amino acid availability." Molecular Biology of the Cell 29, no. 18 (September 2018): 2213–27. http://dx.doi.org/10.1091/mbc.e17-12-0703.
Анотація:
C9orf72 mutations are a major cause of amyotrophic lateral sclerosis and frontotemporal dementia. The C9orf72 protein undergoes regulated recruitment to lysosomes and has been broadly implicated in control of lysosome homeostasis. However, although evidence strongly supports an important function for C9orf72 at lysosomes, little is known about the lysosome recruitment mechanism. In this study, we identify an essential role for WDR41, a prominent C9orf72 interacting protein, in C9orf72 lysosome recruitment. Analysis of human WDR41 knockout cells revealed that WDR41 is required for localization of the protein complex containing C9orf72 and SMCR8 to lysosomes. Such lysosome localization increases in response to amino acid starvation but is not dependent on either mTORC1 inhibition or autophagy induction. Furthermore, WDR41 itself exhibits a parallel pattern of regulated association with lysosomes. This WDR41-dependent recruitment of C9orf72 to lysosomes is critical for the ability of lysosomes to support mTORC1 signaling as constitutive targeting of C9orf72 to lysosomes relieves the requirement for WDR41 in mTORC1 activation. Collectively, this study reveals an essential role for WDR41 in supporting the regulated binding of C9orf72 to lysosomes and solidifies the requirement for a larger C9orf72 containing protein complex in coordinating lysosomal responses to changes in amino acid availability.
5
Amick, Joseph, Agnes Roczniak-Ferguson, and Shawn M. Ferguson. "C9orf72 binds SMCR8, localizes to lysosomes, and regulates mTORC1 signaling." Molecular Biology of the Cell 27, no. 20 (October 15, 2016): 3040–51. http://dx.doi.org/10.1091/mbc.e16-01-0003.
Анотація:
Hexanucleotide expansion in an intron of the C9orf72 gene causes amyotrophic lateral sclerosis and frontotemporal dementia. However, beyond bioinformatics predictions that suggested structural similarity to folliculin, the Birt-Hogg-Dubé syndrome tumor suppressor, little is known about the normal functions of the C9orf72 protein. To address this problem, we used genome-editing strategies to investigate C9orf72 interactions, subcellular localization, and knockout (KO) phenotypes. We found that C9orf72 robustly interacts with SMCR8 (a protein of previously unknown function). We also observed that C9orf72 localizes to lysosomes and that such localization is negatively regulated by amino acid availability. Analysis of C9orf72 KO, SMCR8 KO, and double-KO cell lines revealed phenotypes that are consistent with a function for C9orf72 at lysosomes. These include abnormally swollen lysosomes in the absence of C9orf72 and impaired responses of mTORC1 signaling to changes in amino acid availability (a lysosome-dependent process) after depletion of either C9orf72 or SMCR8. Collectively these results identify strong physical and functional interactions between C9orf72 and SMCR8 and support a lysosomal site of action for this protein complex.
6
Chandra, Sunandini, and C. Patrick Lusk. "Emerging Connections between Nuclear Pore Complex Homeostasis and ALS." International Journal of Molecular Sciences 23, no. 3 (January 25, 2022): 1329. http://dx.doi.org/10.3390/ijms23031329.
Анотація:
Developing effective treatments for neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) requires understanding of the underlying pathomechanisms that contribute to the motor neuron loss that defines the disease. As it causes the largest fraction of familial ALS cases, considerable effort has focused on hexanucleotide repeat expansions in the C9ORF72 gene, which encode toxic repeat RNA and dipeptide repeat (DPR) proteins. Both the repeat RNA and DPRs interact with and perturb multiple elements of the nuclear transport machinery, including shuttling nuclear transport receptors, the Ran GTPase and the nucleoporin proteins (nups) that build the nuclear pore complex (NPC). Here, we consider recent work that describes changes to the molecular composition of the NPC in C9ORF72 model and patient neurons in the context of quality control mechanisms that function at the nuclear envelope (NE). For example, changes to NPC structure may be caused by the dysregulation of a conserved NE surveillance pathway mediated by the endosomal sorting complexes required for the transport protein, CHMP7. Thus, these studies are introducing NE and NPC quality control pathways as key elements in a pathological cascade that leads to C9ORF72 ALS, opening entirely new experimental avenues and possibilities for targeted therapeutic intervention.
7
Alvarez-Mora, Maria Isabel, Gloria Garrabou, Tamara Barcos, Francisco Garcia-Garcia, Ruben Grillo-Risco, Emma Peruga, Laura Gort, et al. "Bioenergetic and Autophagic Characterization of Skin Fibroblasts from C9orf72 Patients." Antioxidants 11, no. 6 (June 8, 2022): 1129. http://dx.doi.org/10.3390/antiox11061129.
Анотація:
The objective of this study is to describe the alterations occurring during the neurodegenerative process in skin fibroblast cultures from C9orf72 patients. We characterized the oxidative stress, autophagy flux, small ubiquitin-related protein SUMO2/3 levels as well as the mitochondrial function in skin fibroblast cultures from C9orf72 patients. All metabolic and bioenergetic findings were further correlated with gene expression data obtained from RNA sequencing analysis. Fibroblasts from C9orf72 patients showed a 30% reduced expression of C9orf72, ~3-fold increased levels of oxidative stress and impaired mitochondrial function obtained by measuring the enzymatic activities of mitochondrial respiratory chain complexes, specifically of complex III activity. Furthermore, the results also reveal that C9orf72 patients showed an accumulation of p62 protein levels, suggesting the alteration of the autophagy process, and significantly higher protein levels of SUMO2/3 (p = 0.03). Our results provide new data reinforcing that C9orf72 cells suffer from elevated oxidative damage to biomolecules and organelles and from increased protein loads, leading to insufficient autophagy and an increase in SUMOylation processes.
8
McAlpine, William, Lei Sun, Kuan-wen Wang, Aijie Liu, Ruchi Jain, Miguel San Miguel, Jianhui Wang, et al. "Excessive endosomal TLR signaling causes inflammatory disease in mice with defective SMCR8-WDR41-C9ORF72 complex function." Proceedings of the National Academy of Sciences 115, no. 49 (November 15, 2018): E11523—E11531. http://dx.doi.org/10.1073/pnas.1814753115.
Анотація:
The SMCR8-WDR41-C9ORF72 complex is a regulator of autophagy and lysosomal function. Autoimmunity and inflammatory disease have been ascribed to loss-of-function mutations of Smcr8 or C9orf72 in mice. In humans, autoimmunity has been reported to precede amyotrophic lateral sclerosis caused by mutations of C9ORF72. However, the cellular and molecular mechanisms underlying autoimmunity and inflammation caused by C9ORF72 or SMCR8 deficiencies remain unknown. Here, we show that splenomegaly, lymphadenopathy, and activated circulating T cells observed in Smcr8−/− mice were rescued by triple knockout of the endosomal Toll-like receptors (TLRs) TLR3, TLR7, and TLR9. Myeloid cells from Smcr8−/− mice produced excessive inflammatory cytokines in response to endocytosed TLR3, TLR7, or TLR9 ligands administered in the growth medium and in response to TLR2 or TLR4 ligands internalized by phagocytosis. These defects likely stem from prolonged TLR signaling caused by accumulation of LysoTracker-positive vesicles and by delayed phagosome maturation, both of which were observed in Smcr8−/− macrophages. Smcr8−/− mice also showed elevated susceptibility to dextran sodium sulfate-induced colitis, which was not associated with increased TLR3, TLR7, or TLR9 signaling. Deficiency of WDR41 phenocopied loss of SMCR8. Our findings provide evidence that excessive endosomal TLR signaling resulting from prolonged ligand–receptor contact causes inflammatory disease in SMCR8-deficient mice.
9
Liang, Chen, Qiang Shao, Wei Zhang, Mei Yang, Qing Chang, Rong Chen, and Jian-Fu Chen. "Smcr8 deficiency disrupts axonal transport-dependent lysosomal function and promotes axonal swellings and gain of toxicity in C9ALS/FTD mouse models." Human Molecular Genetics 28, no. 23 (October 18, 2019): 3940–53. http://dx.doi.org/10.1093/hmg/ddz230.
Анотація:
Abstract G4C2 repeat expansions in an intron of C9ORF72 cause the most common familial amyotrophic lateral sclerosis and frontotemporal dementia (collectively, C9ALS/FTD). Mechanisms and mediators of C9ALS/FTD pathogenesis remain poorly understood. C9orf72 and Smcr8 form a protein complex. Here, we show that expression of Smcr8, like C9orf72, is reduced in C9ALS/FTD mouse models and patient tissues. Since Smcr8 is highly conserved between human and mouse, we evaluated the effects of Smcr8 downregulation in mice. Smcr8 knockout (KO) mice exhibited motor behavior deficits, which resemble those of C9ALS/FTD mouse models, and displayed axonal swellings in their spinal cords and neuromuscular junctions. These deficits are caused by impaired autophagy-lysosomal functions due to disrupted axonal transport in mutant motor neurons. Consistent with its interaction with C9orf72 and their downregulation in patient tissues, Smcr8 deficiency exacerbated autophagy-lysosomal impairment in C9orf72 KO mice. The disease relevance of Smcr8 downregulation was reflected by exacerbated axonal swellings and gain of toxicity pathology arising from Smcr8 haploinsufficiency in a mouse model of C9ALS/FTD. Thus, our in vivo studies suggested that Smcr8 deficiency impairs axonal transport dependent autophagy-lysosomal function and exacerbates axonal degeneration and gain of toxicity in C9ALS/FTD mouse models.
10
Talaia, Gabriel, Joseph Amick, and Shawn M. Ferguson. "Receptor-like role for PQLC2 amino acid transporter in the lysosomal sensing of cationic amino acids." Proceedings of the National Academy of Sciences 118, no. 8 (February 17, 2021): e2014941118. http://dx.doi.org/10.1073/pnas.2014941118.
Анотація:
PQLC2, a lysosomal cationic amino acid transporter, also serves as a sensor that responds to scarcity of its substrates by recruiting a protein complex composed of C9orf72, SMCR8, and WDR41 to the surface of lysosomes. This protein complex controls multiple aspects of lysosome function. Although it is known that this response to changes in cationic amino acid availability depends on an interaction between PQLC2 and WDR41, the underlying mechanism for the regulated interaction is not known. In this study, we present evidence that the WDR41–PQLC2 interaction is mediated by a short peptide motif in a flexible loop that extends from the WDR41 β-propeller and inserts into a cavity presented by the inward-facing conformation of PQLC2. The data support a transceptor model wherein conformational changes in PQLC2 related to substrate transport regulate the availability of the WDR41-binding site on PQLC2 and mediate recruitment of the WDR41-SMCR8-C9orf72 complex to the surface of lysosomes.
Дисертації з теми "C9ORF72 complex":
1
Pietri, David. "Structure and function of the C9ORF72-SMCR8-WDR41 complex and its implication for Amyotrophic Lateral Sclerosis (ALS)." Electronic Thesis or Diss., Strasbourg, 2023. http://www.theses.fr/2023STRAJ087.
Анотація:
La sclérose latérale amyotrophique (SLA ou maladie de Charcot) est la troisième maladie neurodégénérative la plus répandue. La principale cause génétique de la SLA est une expansion de répétitions GGGGCC dans le gène C9ORF72, dont la protéine forme un complexe avec les protéines SMCR8 et WDR41. Afin de mieux comprendre ses fonctions moléculaires, résoudre sa structure était un objectif principal de ma thèse. En parallèle, nous avons découvert que C9ORF72 régule un mécanisme nouvellement décrit de biogenèse de nouveaux lysosomes nommé reformation autophagique des lysosomes (ALR). Ce processus a largement été investigué dans cette thèse afin de mieux comprendre sa régulation, notamment pour la régénération des lysosomes en conditions basales et de privation d’acides aminés. Mon travail révèle un nouveau partenaire du complexe C9ORF72 et une nouvelle fonction de ce complexe dans la biogenèse des lysosomes. Ces résultats pourraient ainsi expliquer le dysfonctionnement des lysosomes et la neurodégénérescence observés dans la SLA, ce qui pourrait ainsi ouvrir de nouvelles voies thérapeutiques pour cette maladie dévastatriceAmyotrophic lateral sclerosis (ALS or Charcot disease) is the third most common neurodegenerative disease. The main genetic cause of ALS is an expansion of GGGGCC repeats in the C9ORF72 gene which protein forms a complex with the SMCR8 and WDR41 proteins. To better understand its molecular functions, solving its structure was a main goal of my thesis. In parallel, we discovered that C9ORF72 regulates a newly described mechanism of biogenesis of newly-formed lysosomes, called autophagic lysosome reformation (ALR). This process has been extensively investigated during my thesis, in order to better understand its regulation, particularly for the regeneration of lysosomes in basal conditions and amino acid deprivation. My work reveals a new partner of the C9ORF72 complex as a novel function in lysosome biogenesis. These results could thus explain the dysfunction of lysosomes and neurodegeneration observed in ALS, which open new therapeutic ways for this devastating disease