Academic literature on the topic 'Spinocerebellar Degenerations'

As ataxias hereditárias autossômicas recessivas compõem um grupo de doenças heterogêneas, que necessitam de criteriosa avaliação clínica, de exames complementares e, algumas vezes, de testes genéticos para o diagnóstico. A partir da revisão da literatura, foi elaborado um algoritmo para auxiliar a investigação diagnóstica deste grupo. Esta tese tem como objetivo apresentar os resultados da investigação de três formas de ataxias recessivas: 1. Síndrome de Joubert, caracterizada por hipotonia precoce, atraso do desenvolvimento neuropsicomotor, ataxia e padrão respiratório irregular no período neonatal ou anormalidades na motricidade ocular extrínseca. Apresenta amplo espectro clínico, assim como heterogeneidade genética. Alterações renal, hepática e da retina são freqüentes. A presença de hipoplasia do vermis cerebelar, alongamento dos pedúnculos cerebelares superiores e aumento da fossa interpeduncular, aos cortes axiais da ressonância magnética (RM) do encéfalo, constituem o sinal do dente molar, considerado critério radiológico obrigatório para o diagnóstico. Aqui é apresentada uma série de cinco pacientes que preenchem critérios clínicos e radiológico de síndrome de Joubert e tem grande variabilidade fenotípica: duas crianças têm a forma pura (subtipo 1), uma tem associadamente retinopatia (subtipo 3), uma tem amaurose congênita de Leber e alteração renal (subtipo 4) e a outra apresenta associadamente coloboma corioretiniano e alterações hepáticas (subtipo 5); 2. Ataxia com Deficiência de Vitamina E, que apresenta fenótipo semelhante ao da ataxia de Friedreich, progressão mais lenta, baixo nível sérico de -tocoferol e é tratável com reposição da vitamina E. Frequente no sul da Itália e norte da África, sem relatos no Brasil. Foram investigados quatro pacientes pertencentes a duas famílias: três apresentavam o quadro clínico típico acompanhado de distonia em mãos, manifestação pouco relatada, mas que pode contribuir para a diferenciação clínica com ataxia de Friedreich. O outro paciente foi identificado em fase pré-sintomática, após o diagnóstico ser estabelecido em dois irmãos, e permanece com sinais sutis de alteração do equilíbrio após de 5 anos de reposição de vitamina E. Nos demais, a reposição de vitamina E promoveu melhora dos sintomas e impediu que a doença se agravasse; 3. Xantomatose Cerebrotendínea, que está relacionada à alteração no metabolismo do colesterol, com redução na produção dos ácidos biliares e acúmulo de colestanol, um metabólito tóxico. Catarata congênita ou juvenil e diarréia crônica são manifestações precoces. Ataxia cerebelar, paraparesia espástica, declínio cognitivo e xantomas tendíneos completam o quadro clínico. Na RM do encéfalo, a presença de hipersinal nos núcleos denteados, nas sequências T2-pesada e FLAIR, é sugestiva da doença. Três pacientes, pertencentes a duas famílias, com alterações clínicas e radiológica foram investigados. Em todos, o colestanol sérico encontravase elevado. A espectrocopia por RM detectou no cerebelo pico em 1,2-1,4 ppm, sugestivo de lipídio, achado até o momento não descrito. Após início do tratamento com ácido quenodeoxicólico, observou-se melhora da marcha.
Autosomal recessive hereditary ataxias belong to a group of heterogeneous disorders, for which detailed clinical evaluation, ancillary exams, and sometimes, genetic tests, are required for diagnosis. After literature review, an algorithm was built to help the investigation of this group. The objective of this thesis is to present the results of investigation of three forms of recessive ataxias: 1. Joubert syndrome is a condition characterized by early hypotonia, developmental delay, ataxia and neonatal respiratory disturbances or abnormal eye movement. It has a wide clinical spectrum and is genetically heterogeneous. Renal, hepatic and retina abnormalities are often seen. A combination of midline cerebellar vermis hypoplasia, deepened interpenducular fossa, and thick, elongated superior cerebellar penduncles gives to the axial view of the midbrain an appearance of a molar tooth at brain magnetic ressonance image (MRI) study. Molar tooth sign is considered as obligatory radiologic criteria to diagnosis. In this study we present a series of five patients that have clinical and radiologic criteria to Joubert syndrome and a large phenotypic variability: Two children have a pure form (subgroup 1), one child has an associated retinopathy (subgroup 3), the other has Leber congenital amaurosis and kidney abnormalitties (subgroup 4), and another has chorioretinal coloboma and hepatic abnormalities (subgroup 5); 2. Ataxia with vitamin E deficiency, which has a phenotype similar to Friederich ataxia but slowest progression, is characterized by low levels of serum -tocopherol and is treatable with vitamin E. This ataxia is common in South Italy and North Africa, but was not reported in Brazil. Four patients from two different families were studied. Three of them have typical clinical features and hands dystonia, a probably underreported feature which might helps its distinction from Friedreich ataxia. The other case was identified in a presymptomatic stage, after family investigation. After five years of treatment with vitamin E, subtle balance disturbance was still present. The remaing three patientes improved with vitamin E supplementation and disease progression stopped; 3. Cerebrotendinous xantomathosis (CTX) is a disorder of cholesterol metabolism, characterized by reduction of bile acid synthesis and accumulation of cholestanol, a toxic metabolic. Congenital or juvenile cataract and chronic diarrhea are early manifestations. Cerebellar ataxia, spastic paraplegia, cognitive impairment and tendinous xanthomas are also seen. Brain MRI T2-weighted and FLAIR sequences disclosed dentate nucleus hypersignal, a quite feature in CTX. Three patients from two different families, with clinical and radiologic features were studied. In all, serum cholestanol was elevated. MRI spectroscopy demonstrated in cerebellum a peak in 1,2-1,4 ppm, which is an possibly a lipid, not previously described. Treatment with chenodeoxycholic acid improved their gait.

Saccadic and vestibular-evoked eye movements are similar in that their three-dimensional kinematic properties show eye position-dependence. When the line of sight is directed towards an eccentric target, the eye velocity axis tilts in a manner that depends on the instantaneous position of the eye in the head, with the magnitude of tilt also depending on whether the eye movement is saccadic or vestibular-evoked. The mechanism responsible for producing eye velocity axis tilting phenomena is not well understood. Some authorities have suggested that muscle pulleys in the orbit are critical for implementing eye velocity axis tilting, while others have suggested that the cerebellum plays an important role. In the current study, three-dimensional eye and head rotation data were acquired, using the magnetic search coil technique, to confirm the presence of eye position-dependent eye velocity axis tilting during saccadic eye movements. Both normal humans and humans with cerebellar atrophy were studied. While the humans with cerebellar atrophy were noted to have abnormalities in the two-dimensional metrics and consistency of their saccadic eye movements, the eye position-dependent eye velocity axis tilts were similar to those observed in the normal subjects. A mathematical model of the human saccadic and vestibular systems was utilized to investigate the means by which these eye position-dependent properties may arise for both types of eye movement. The predictions of the saccadic model were compared with the saccadic data obtained in the current study, while the predictions of the vestibular model were compared with vestibular-evoked eye movement data obtained in a previous study. The results from the model simulations suggest that the muscle pulleys are responsible for bringing about eye position-dependent eye velocity axis tilting for both saccadic and vestibular-evoked eye movements, and that these phenomena are not centrally programmed.

Master of Science in Medicine
Saccadic and vestibular-evoked eye movements are similar in that their three-dimensional kinematic properties show eye position-dependence. When the line of sight is directed towards an eccentric target, the eye velocity axis tilts in a manner that depends on the instantaneous position of the eye in the head, with the magnitude of tilt also depending on whether the eye movement is saccadic or vestibular-evoked. The mechanism responsible for producing eye velocity axis tilting phenomena is not well understood. Some authorities have suggested that muscle pulleys in the orbit are critical for implementing eye velocity axis tilting, while others have suggested that the cerebellum plays an important role. In the current study, three-dimensional eye and head rotation data were acquired, using the magnetic search coil technique, to confirm the presence of eye position-dependent eye velocity axis tilting during saccadic eye movements. Both normal humans and humans with cerebellar atrophy were studied. While the humans with cerebellar atrophy were noted to have abnormalities in the two-dimensional metrics and consistency of their saccadic eye movements, the eye position-dependent eye velocity axis tilts were similar to those observed in the normal subjects. A mathematical model of the human saccadic and vestibular systems was utilized to investigate the means by which these eye position-dependent properties may arise for both types of eye movement. The predictions of the saccadic model were compared with the saccadic data obtained in the current study, while the predictions of the vestibular model were compared with vestibular-evoked eye movement data obtained in a previous study. The results from the model simulations suggest that the muscle pulleys are responsible for bringing about eye position-dependent eye velocity axis tilting for both saccadic and vestibular-evoked eye movements, and that these phenomena are not centrally programmed.

Adult neural precursor cells (NPCs) are a heterogeneous population of mitotically active, self-renewing multipotent cells of both adult and developing CNS. They can be expanded in vitro in the presence of mitogens. The B05 transgenic SCA1 mice, expressing human ataxin-1 with an expanded polyglutamine tract in cerebellar Purkinje cells (PCs), recapitulate many pathological and behavioral characteristics of the neurodegenerative disease spinocerebellar ataxia type 1 (SCA1), including progressive ataxia and PC loss. We transplanted neural precursor cells (NPCs) derived from the subventricular zone of GFP-expressing adult mice into the cerebellar white matter of SCA1 mice when they showed absent (5 weeks), initial (13 weeks) and significant PC loss (24 weeks). A stereological count demonstrates that mice with significant cell loss exhibit highest survival of grafted NPCs and migration to the vicinity of PCs as compared to wt and younger grafted animals. These animals showed improved motor skills as compared to sham animals. Confocal analysis and profiling shows that many of implanted cells present in the cerebellar cortex have formed gap junctions with host PCs and express connexin43. Grafted cells did not adopt characteristics of PCs, but stereological and morphometric analysis of the cerebellar cortex revealed that grafted animals had more surviving PCs and a better preserved morphology of these cells than the control groups. Perforated patch clamp recordings revealed a normalization of the PC basal membrane potential, which was abnormally depolarized in sham-treated animals. No significant increase in levels of several neurotrophic factors was observed, suggesting, along with morphological observation, that the neuroprotective effect of grafted NPCs was mediated by direct contact with the host PCs. In this study, evidence for a neuroprotective effect came, in addition to motor behavior improvement, from stereological and electrophysiological analyses and suggest that timing of stem cell delivery is important to determine its therapeutic effect.

In a brain stem cell niche, NSCs reside in a complex cellular and extracellular microenvironment comprising their own progeny, ependymal cells, numerous blood vessels and various extracellular matrix molecules. Recently, it was reported that blood vessel ECs-NSCs crosstalk plays an important role in tissue homeostasis. Bloodstream offers a natural delivery vehicle especially in case of diffuse neurodegenerative diseases which require widespread distribution of exogenous cells. As NSCs are confronted with blood-brain barrier endothelial cells (BBB-ECs) before they can enter into brain parenchyma, we investigated their interaction using primary cultures in an in vitro BBB model. We isolated human fetal neural precursor cells (hfNPCs) from aborted fetal brain tissues and expanded in vitro. We showed that in an in vitro model, human BBB endothelium induces the rapid differentiation of hfNPCs and allows them to cross the endothelial monolayer, with the differentiated progeny remaining in close contact with endothelial cells. These results are not reproduced when using a non-BBB endothelium and are partly dependent on the cytokine MCP1. Our data suggest that, in the presence of attractive signals released by a damaged brain, intravascularly administered NPCs can move across an intact BBB endothelium and differentiate in its vicinity. Overall, our findings have implications for the development of cellular therapies for cerebellar degenerative diseases and understanding of the brain stem cell niche.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished

Lam Wun.
Thesis (M.Phil.)--Chinese University of Hong Kong, 2005.
Includes bibliographical references (leaves 140-153).
Abstracts in English and Chinese.
ABSTRACT --- p.i
ACKNOWLDGEMENT --- p.iii
TABLE OF CONTENT --- p.iv
ABBREVIATIONS --- p.x
LISTS OF TABLES --- p.xi
LISTS OF FIGURES --- p.xii
Chapter 1. --- INTRODUCTION
Chapter 1.1 --- Neurodegeneration and triplet repeat diseases --- p.1
Chapter 1.2 --- Polyglutamine diseases --- p.2
Chapter 1.3 --- Polyglutamine nuclear inclusions --- p.4
Chapter 1.3.1 --- Kinetics of polyglutamine nuclear inclusion formation --- p.4
Chapter 1.3.2 --- Roles of protein inclusions in neurodegeneration --- p.7
Chapter 1.4 --- Polyglutamine pathogenic pathways --- p.8
Chapter 1.4.1 --- Protein depletion theory --- p.9
Chapter 1.4.2 --- Induction of apoptotic pathways --- p.13
Chapter 1.5 --- Previous study on NI proteins --- p.14
Chapter 1.6 --- Drosophila model for studying polyglutamine diseases --- p.15
Chapter 1.6.1 --- Drosophila model for studying human diseases --- p.15
Chapter 1.6.2 --- GAL4/UAS gene expression system --- p.15
Chapter 1.6.3 --- Drosophila polyglutamine models --- p.17
Chapter 1.7 --- Objectives of the study --- p.21
Chapter 2. --- MATERIALS AND METHODS
Chapter 2.1 --- Drosophila genetics --- p.22
Chapter 2.1.1 --- Drosophila culture --- p.22
Chapter 2.1.2 --- GAL4/UAS gene expression system --- p.22
Chapter 2.1.3 --- Eye phenotypic analysis --- p.25
Chapter 2.1.4 --- Polyglutamine fly models --- p.25
Chapter 2.1.5 --- Generation and characterization of GFP-polyglutamine transgenic fly models --- p.25
Chapter 2.2 --- Proteomic identification of nuclear inclusion proteins --- p.26
Chapter 2.2.1 --- Proteomic identification of NI proteins by SDS-insolubility of NIs --- p.26
Chapter 2.2.2 --- Proteomic identification of NI proteins by FA-solubility of NIs --- p.27
Chapter 2.2.2.1 --- Approach overview --- p.27
Chapter 2.2.2.2 --- Sample preparation for two-dimensional gel electrophoresis --- p.27
Chapter 2.2.2.3 --- Two-dimensional gel electrophoresis --- p.29
Chapter 2.2.2.4 --- Polyacrylamide gel staining --- p.31
Chapter 2.2.2.5 --- Computer analysis of 2D patterns --- p.31
Chapter 2.2.2.6 --- In-gel trypsin digestion --- p.32
Chapter 2.2.2.7 --- Mass spectrometric analysis --- p.33
Chapter 2.2.3 --- Detection of NIs by flow cytometry --- p.34
Chapter 2.3 --- SDS-polyacrylamide gel electrophoresis (SDS-PAGE) --- p.34
Chapter 2.3.1 --- Sample preparation for SDS-PAGE --- p.34
Chapter 2.3.2 --- SDS-PAGE --- p.35
Chapter 2.4 --- Immunodetection --- p.36
Chapter 2.4.1 --- Electroblotting --- p.36
Chapter 2.4.2 --- Western blotting --- p.36
Chapter 2.4.3 --- Filter trap assay --- p.37
Chapter 2.5 --- Sav antibody production --- p.38
Chapter 2.5.1 --- Sav peptide synthesis --- p.38
Chapter 2.5.2 --- Rabbit immunization --- p.38
Chapter 2.6 --- Cryosectioning and immunostaining of adult fly heads --- p.39
Chapter 2.7 --- Alcohol dehydrogenase assay --- p.40
Chapter 2.8 --- Semi-quantitative reverse transcription- Polymerase Chain Reaction --- p.41
Chapter 2.8.1 --- Total RNA preparation from fly heads --- p.41
Chapter 2.8.2 --- Reverse transcription- Polymerase Chain Reaction (RT-PCR) --- p.41
Chapter 2.9 --- Reagents and buffers --- p.42
Chapter 3. --- RESULTS
Chapter 3.1 --- Transgenic polyglutamine fly models --- p.48
Chapter 3.1.1 --- Characteristics of MJD polyglutamine fly model --- p.48
Chapter 3.1.1.1 --- Overexpression of expanded truncated human MJD proteins in Drosophila causes eye degeneration --- p.49
Chapter 3.1.1.2 --- Overexpression of expanded truncated human MJD proteins in Drosophila results in nuclear inclusion formation --- p.49
Chapter 3.1.1.3 --- Formic acid dissolves fly polyglutamine nuclear inclusions --- p.51
Chapter 3.1.1.3.1 --- Formic acid dissolves fly polyglutamine NIs as shown by Western blot analysis --- p.51
Chapter 3.1.1.3.2 --- Formic acid dissolves fly polyglutamine NIs as shown by filter trap assay --- p.53
Chapter 3.1.2 --- Summary --- p.55
Chapter 3.2 --- Proteomic identification of nuclear inclusion (NI) proteins --- p.56
Chapter 3.2.1 --- Proteomic identification of NI proteins by SDS-insolubility of NIs --- p.56
Chapter 3.2.2 --- Proteomic identification of NI proteins by FA-solubility of NIs --- p.63
Chapter 3.2.2.1 --- Two-dimensional gels showing differential protein spots as potential NI proteins --- p.63
Chapter 3.2.2.2 --- NI protein candidates identified by the 2D approach --- p.75
Chapter 3.2.3 --- Study of polyglutamine NI proteins by flow cytometry analysis --- p.90
Chapter 3.2.3.1 --- Detection of fly polyglutamine NIs by flow cytometry --- p.90
Chapter 3.2.3.2 --- Characterization of a new GFP-polyglutamine fly model --- p.92
Chapter 3.3 --- Characterization of the nuclear inclusion protein candidates --- p.96
Chapter 3.3.1 --- Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) --- p.96
Chapter 3.3.1.1 --- Confirmation of GAPDH as a NI protein --- p.97
Chapter 3.3.1.2 --- Discussion --- p.97
Chapter 3.3.2 --- Receptor of activated protein kinase C (RACK1) --- p.99
Chapter 3.3.2.1 --- Confirmation of RACK1 as a NI protein --- p.99
Chapter 3.3.2.1.1 --- Colocalization of RACK1 with NIs --- p.99
Chapter 3.3.2.1.2 --- Formic Acid extracts RACK1 from NIs --- p.101
Chapter 3.3.2.2 --- Reduction of soluble RACK1 protein level in polyglutamine fly --- p.101
Chapter 3.3.2.2.1 --- Soluble RACK1 protein level reduced in polyglutamine fly --- p.101
Chapter 3.3.2.2.2 --- RACK1 transcript level remains unchanged in polyglutamine fly --- p.103
Chapter 3.3.2.3 --- Overexpression of RACK 1 partially suppresses polyglutamine degeneration --- p.105
Chapter 3.3.2.4 --- Discussion --- p.107
Chapter 3.3.3 --- Warts (Wts) --- p.111
Chapter 3.3.3.1 --- Overexpression of Wts partially suppresses polyglutamine degeneration --- p.111
Chapter 3.3.3.2 --- Wts mutant slightly enhances polyglutamine degeneration --- p.113
Chapter 3.3.3.3 --- Genetic analysis of Warts pathway in polyglutamine pathogenesis --- p.113
Chapter 3.3.3.3.1 --- Overexpression of Salvador partially suppresses polyglutamine degeneration --- p.116
Chapter 3.3.3.3.2 --- Hpo mutant slightly enhances polyglutamine degeneration --- p.119
Chapter 3.3.3.3.3 --- Overexpression of DIAP1 partially suppresses polyglutamine degeneration --- p.119
Chapter 3.3.3.4 --- Discussion --- p.121
Chapter 3.3.4 --- Alcohol dehydrogenase (Adh) --- p.122
Chapter 3.3.4.1 --- Adh activity is reduced in polyglutamine flies --- p.122
Chapter 3.3.4.2 --- Overexpression of Hsp70 partially restores the reduced Adh activity in polyglutamine flies --- p.122
Chapter 3.3.4.3 --- Discussion --- p.125
Chapter 3.3.5 --- Genetic analysis of other NI protein candidates --- p.127
Chapter 3.3.5.1 --- Overexpression of CG7920 protein partially suppresses polyglutamine degeneration --- p.127
Chapter 3.3.5.2 --- Pten dsRNA slightly enhances polyglutamine degeneration --- p.129
Chapter 3.3.6 --- Summary --- p.131
Chapter 4. --- DISSCUSSION
Chapter 4.1 --- Protein depletion theory --- p.133
Chapter 4.2 --- Comparison of different approaches for identification of NI proteins --- p.134
Chapter 4.3 --- Long-term significance --- p.136
Chapter 4.4 --- Future studies --- p.137
Chapter 4.4.1 --- Characterization of other NI protein candidates --- p.137
Chapter 4.4.2 --- Study of NI proteins by an alternative approach --- p.137
Chapter 4.4.3 --- Study of NI proteins using other polyglutamine fly models --- p.137
Chapter 5. --- CONCLUSION --- p.139
Chapter 6. --- REFERENCES --- p.140

This chapter explores the historical development of understanding about the structure, function, and disorders of the cerebellum. The chosen papers represent the following development: the discovery that the cerebellum is concerned with movement control rather than movement generation; the first recognition of a distinct spinocerebellar disorder; recognition of the existence of dominantly-inherited ataxias; the delineation of the classic motor features of ataxia; the formal recognition of paraneoplastic cerebellar degenerations; the description of truncal ataxia due to anterior vermal damage in chronic alcoholics; the demonstration of long-term depression at the parallel fibre; the discovery of the first gene (ATXN 1) for a dominantly-inherited spinocerebellar ataxia; the revelation that episodic ataxia type 2 is an ion channel disorder; and the recognition of a cerebellar role in cognition and emotional regulation.

This chapter examines sleep–wake disturbances occurring in the most common neurodegenerative disorders. It reviews sleep alterations in Alzheimer disease and dementia with Lewy bodies. It also discusses sleep problems in progressive supranuclear palsy, corticobasal degeneration, Huntington disease, and spinocerebellar ataxias. Status dissociatus as an extreme form of sleep alteration in advanced neurodegenerative diseases is also considered. The chapter reviews the key points for the treatment of disrupted sleep in neurodegenerative disorders, with a focus on pharmacological and nonpharmacological interventions to improve sleep continuity. It also summarizes paraphysiological age-related changes in sleep patterns and discusses indications and procedures for clinical and instrumental assessment of sleep disorders in neurodegenerative disorders.

Background: Spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of progressive autosomal disorders of dominant inheritance with a gradual degeneration of the cerebellum and related pathways [1]. This leads to a movement disorder, loss of balance and coordination, accompanied by slurred speech [2]. Among the approximately 40 types of SCA, the spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most clinically heterogeneous [3]. It involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems [2]. Objectives: Understand the clinical findings of SCA3. Methods: The review was based on papers from SciELO and LILACS databases. Articles presented in full, written in English or Portuguese, were researched. Results: SCA3 is a consequence of the ATXN3 gene modification, which generates pathogenic repeated expansions of trinucleotides CAG, leading to polyglutamine coding. The common clinical phenotype includes the presentation of symptoms such as cerebellar ataxia, ophthalmoplegia, spasticity, basal ganglia symptoms, sensory symptoms, amyotrophy, including facial atrophy and fasciculations [4]. In addition, atrophy of the cerebellar vermis, hemispheres, brainstem and medial cerebellar peduncle are visualized on MRI in the early stages, resulting in an enlargement of the fourth ventricle. Furthermore, changes also occur in the caudate nucleus, putamen and upper cerebellar peduncle [5]. Conclusion: Through data analysis, there is a necessity to know the clinical and pathological characteristics of SCA3. This neurological disorder causes suffering for the patients, since it is a highly debilitating serious condition.