脊髓小脑性共济失调的分子遗传学进展

脊髓小脑性共济失调是一类由于遗传因素造成的单基因神经系统变性性疾病 ,不同位点的三核苷酸重复扩增导致不同的遗传亚型。已经发现 2 2种亚型的脊髓小脑性共济失调 ,多数是由于致病基因内存在 CAG重复片段异常扩增 ,导致含有多聚谷氨酰胺链的突变蛋白在细胞核内沉积形成核内包涵体。本文就其最近的分子遗传学进展作简要综述     

脊髓小脑性共济失调的分子遗传学进展

脊髓小脑性共济失调是一类由于遗传因素造成的单基因神经系统变性性疾病，不同位点的三核苷酸重复扩增导致不同的遗传亚型。已经发现22种亚型的脊髓小脑性共济失调，多数是由于致病基因内存在CAG重复片段异常扩增，导致含有多聚谷氨酰胺链的突变蛋白在细胞核内沉积形成核内包涵体。本文就其最近的分子遗传学进展作简要综述。     

脊髓小脑共济失调3型致病蛋白ataxin-3毒性损伤机制

脊髓小脑共济失调3型是我国常见的三核苷酸序列异常扩增导致的常染色体显性遗传疾病。其致病蛋白ataxin-3具有泛素结合蛋白功能，调节细胞蛋白质稳态；同时ataxin-3蛋白功能可能还与细胞骨架等相关。异常扩展突变的ataxin-3有聚集倾向，在细胞内募集多种蛋白成分形成蛋白聚集体或包涵体，导致基因转录异常、蛋白稳态失衡、能量代谢障碍、运输障碍等多种细胞功能损伤以致细胞凋亡，进而影响细胞功能而致病。结合目前对多聚谷氨酸异常扩展突变疾病的研究现状，此文就现有的脊髓小脑共济失调3型致病机制进行综述。     

非编码区核苷酸重复扩增导致的三种脊髓小脑型共济失调亚型分子基础

遗传性脊髓小脑型共济失调(hereditary spinocerebellar ataxias,SCAs)的发病大部分与基因编码区三核苷酸CAG/CAA的异常重复有关,而SCA8、SCA10、SCA12的发病分别与致病基因非编码区CTA/CTG、ATILT和CAG的异常重复突变有关;近来的研究主要集中在3种亚型的遗传特征和发病机制上面,如核苷酸重复的不稳定性不同外显率的改变、疾病遗传的性别偏倚和遗传早现现象等.由于非编码区核苷酸重复对翻译成多聚谷氨酰胺蛋白的影响不大,3种SCA亚型的发病机制和其它SCAS严型完全不同,核苷酸的异常重复对DNA转录的干扰、转录后含异常核苷酸重复的RNA的毒性作用以及重复序列不同方向上的双向转录机制在3种SCA业型的发病机制中可能起到了关键作用.     

多聚谷氨酰胺链调控beclin 1依赖性自噬

正有9种神经退行性疾病是由不同蛋白的多聚谷氨酰胺(polyglutamine,Poly Q)链(tracts)延长所导致的,例如亨廷顿病(Huntington’s disease)中的亨廷顿蛋白(huntingtin)和3型脊髓小脑共济失调(spinocerebellar ataxia type 3,SCA3)中的共济失调蛋白3(ataxin 3)。发病年龄随着这些蛋白Poly Q长度的增加而下降,并且这些蛋白的正常长度也发生改变。离体Poly Q链     

在CAG重复序列导致的疾病中出现的核包含体是有毒的,还是有保护作用的?

在所涉及基因的编码区,由于CAG重复序列的扩张而引起一系列神经变性疾病,包括亨廷顿舞蹈症（HD）和Ⅰ型脊髓小脑运动失调症．经研究发现在它们的蛋白质突变产物中出现多聚谷酰胺．根据这些疾病中突变基因同源性的缺乏、其遗传性的主要特征以及敲除相关基因的小鼠没有临床症状的事实可得到以下结论扩张的多聚谷酰胺束是涉及功能突变的病理性改变．CAG重复序列紊乱的病人和小鼠模型中出现的存在多聚谷酰胺束的蛋白聚集体、核包含体说明这些蛋白聚集体是有毒性的和致病性的．最近的两篇文献对这些假设提出疑问。Klement及其同事已经建立…     

脊髓小脑共济失调研究新进展

遗传性脊髓小脑共济失调是一大类迟发型神经退化性疾病 ,是由三核苷酸 (或五核苷酸 )动态突变扩展引起 ,呈常染色体显性遗传 ,具有多神经病理症状 ,脊髓小脑萎缩 ,神经元丢失等。临床症状为迟发性共济失调。随着人类基因组研究的发展 ,大约有 18种基因位点被发现 ,下面就脊髓小脑共济失调的分类、表型特征、分子基础、致病机制等作详细的综述。     

脊髓小脑共济失调研究新进展

遗传性脊髓小脑共济失调是一大类迟发型神经退化性疾病，是由三核苷酸(或五核苷酸)动态突变扩展引起，呈常染色体显性遗传，具有多神经病理症状，脊髓小脑萎缩，神经元丢失等。临床症状为迟发性共济失调。随着人类基因组研究的发展，大约有18种基因位点被发现，下面就脊髓小脑共济失调的分类、表型特征、分子基础、致病机制等作详细的综述。     

一个遗传性脊髓小脑型共济失调大家系的致病基因分析

目的探讨一个遗传性脊髓小脑型共济失调（SCA）大家系的遗传特点和基因突变分析。方法对一个遗传性脊髓小脑型共济失调（SCA）大家系进行家系调查,绘制系谱图,抽取家系成员外周血,采用聚合酶链反应和毛细管电泳对致病基因进行分析检测。结果该家系的遗传性脊髓小脑型共济失调（SCA）为常染色体显性遗传,6代45人中有15人为SCA患者,4人为携带致病基因的无症状患者。患者ATX3基因的CAG三核苷酸重复65-73次。结论该家系为常染色体显性遗传的SCA3型（SCA/MJD）,患者基因突变检测分析显示异常扩增的CAG突变数与发病年龄呈明显的负相关。基因突变检测在疾病诊断和早期发现无症状患者方面有重要作用,从遗传生殖角度阻断该病的遗传有重要意义。     

中国大陆遗传性脊髓小脑型共济失调患者PURATROPHIN-1基因c.-16C＞T突变研究

目的 研究中国大陆遗传性脊髓小脑型共济失调(spinocerebellar ataxia,scA)患者PURATROPHIN-1 c.-16C＞T突变分布.方法 应用聚合酶链反应.限制性片段长度多态技术,对已经排除了SCA1、SCA2、SCA3、SCA6、SCA7、SCA17和齿状核.红核.苍白球路易体萎缩的68个常染色体显性遗传SCA家系的先证者及119例散发SCA患者进行PURATROPHIN-1基因c.-16C＞T突变检测.结果 未发现PUPURATROPHIN-1基因c.-16C＞T突变.结论 PURATROPHIN-1基因c.-16C＞T突变在中国大陆SCA人群中罕见.     

Toward understanding Machado-Joseph disease

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies. ATXN3 is a deubiquitinating enzyme (DUB) whose highly specialized properties suggest that it participates in ubiquitin-dependent proteostasis. By virtue of its interactions with VCP, various ubiquitin ligases and other ubiquitin-linked proteins, ATXN3 may help regulate the stability or activity of many proteins in diverse cellular pathways implicated in proteotoxic stress response, aging, and cell differentiation. Expansion of the polyQ tract in ATXN3 is thought to promote an altered conformation in the protein, leading to changes in interactions with native partners and to the formation of insoluble aggregates. The development of a wide range of cellular and animal models of MJD has been crucial to the emerging understanding of ATXN3 dysfunction upon polyQ expansion. Despite many advances, however, the principal molecular mechanisms by which mutant ATXN3 elicits neurotoxicity remain elusive. In a chronic degenerative disease like MJD, it is conceivable that mutant ATXN3 triggers multiple, interconnected pathogenic cascades that precipitate cellular dysfunction and eventual cell death. A better understanding of these complex molecular mechanisms will be important as scientists and clinicians begin to focus on developing effective therapies for this incurable, fatal disorder.     

Ataxin-2 polyQ expansions in FTLD-ALS spectrum disorders in Flanders-Belgian cohorts

There exists considerable clinical and pathological overlap between frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), which implies that these 2 neurodegenerative conditions share common pathogenic mechanisms. Recently, intermediate-length (27-33) polyglutamine (polyQ) expansions in ataxin-2 (ATXN2) have been associated with increased risk for ALS, while expansions of > 34 repeats are known to cause spinocerebellar ataxia type 2 (Sca-2). We identified in 72 ALS patients one patient with a 33 polyQ expansion that was absent in 810 control individuals. This allele was also found in one patient with concomitant ALS-Sca-2. In contrast, in a Flanders-Belgian series of 270 FTLD and 22 FTLD-ALS patients, we found no association with intermediate-length polyQ expansions nor did we observe patient-specific long expansions in agreement with the recent observation in a screening of a substantial sized cohort of patients with diverse neurodegenerative brain diseases. Our results provide further support to the notion that ATXN2 associated polyglutamine amplification is specific to the ALS-end of the FTLD-ALS disease spectrum.     

Progressive retinal degeneration and dysfunction in R6 Huntington's disease mice

Huntington's disease (HD) and spinocerebellar ataxia type 7 (SCA7) belong to a group of progressive neurodegenerative diseases caused by polyglutamine (polyQ) expansions. SCA7 is the only one to display degeneration in the retina, a tissue usually spared in HD. We previously described a SCA7 transgenic retinal model expressing mutant full length ataxin-7 in rod photoreceptors. These mice develop a severe and characteristic retinopathy. We show here that R6 transgenic mice, which reproduce many features of HD, express mutant huntingtin in the retina leading to strong vision deficiencies and retinal dystrophy. These two different polyQ mouse models exhibit comparable early and progressive retinal degeneration and dysfunction. These abnormalities are reminiscent of other retinal degeneration phenotypes (in particular rd7/rd7 mice) where photoreceptor cell loss occurs. Retinopathy in R6 and R7E models can be monitored in living mice by ERG and fundus examination, which can facilitate in vivo evaluation of therapeutic agents in polyQ disorders.     

On the distribution of intranuclear and cytoplasmic aggregates in the brainstem of patients with spinocerebellar ataxia type 2 and 3

The polyglutamine (polyQ) diseases are a group of genetically and clinically heterogeneous neurodegenerative diseases, characterized by the expansion of polyQ sequences in unrelated disease proteins, which form different types of neuronal aggregates. The aim of this study was to characterize the aggregation pathology in the brainstem of spinocerebellar ataxia type 2 (SCA2) and 3 (SCA3) patients. For good recognition of neurodegeneration and rare aggregates, we employed 100 µm PEG embedded brainstem sections, which were immunostained with the 1C2 antibody, targeted at polyQ expansions, or with an antibody against p62, a reliable marker of protein aggregates. Brainstem areas were scored semiquantitatively for neurodegeneration, severity of granular cytoplasmic staining (GCS) and frequency of neuronal nuclear inclusions (NNI). SCA2 and SCA3 tissue exhibited the same aggregate types and similar staining patterns. Several brainstem areas showed statistically significant differences between disease groups, whereby SCA2 showed more severe GCS and SCA3 showed more numerous NNI. We observed a positive correlation between GCS severity and neurodegeneration in SCA2 and SCA3 and an inverse correlation between the frequency of NNI and neurodegeneration in SCA3. Although their respective disease proteins are unrelated, SCA2 and SCA3 showed the same aggregate types. Apparently, the polyQ sequence alone is sufficient as a driver of protein aggregation. This is then modified by protein context and intrinsic properties of neuronal populations. The severity of GCS was the best predictor of neurodegeneration in both disorders, while the inverse correlation of neurodegeneration and NNI in SCA3 tissue implies a protective role of these aggregates.     

Creatine-supplemented diet extends Purkinje cell survival in spinocerebellar ataxia type 1 transgenic mice but does not prevent the ataxic phenotype

It is not known why expression of a protein with an expanded polyglutamine region is pathogenic in spinocerebellar ataxia, Huntington's disease and several other neurodegenerative diseases. Dietary supplementation with creatine improves survival and motor performance and delays neuronal atrophy in the R6/2 transgenic mouse model of Huntington's disease. These effects may be due to improved energy and calcium homeostasis, enhanced presynaptic glutamate uptake, or protection of mitochondria from the mitochondrial permeability transition. We tested the effects of a 2% creatine-supplemented diet and treatment with taurine-conjugated ursodeoxycholic acid, a bile constituent that can inhibit the mitochondrial permeability transition, on ataxia and Purkinje cell survival in a transgenic model of spinocerebellar ataxia type 1. After 24 weeks, transgenic mice on the 2% creatine diet had cerebellar phosphocreatine levels that were 72.5% of wildtype controls, compared to 26.8% in transgenic mice fed a control diet. The creatine diet resulted in maintenance of Purkinje cell numbers in these transgenic mice at levels comparable to wildtype controls, while transgenic mice fed a control diet lost over 25% of their Purkinje cell population. Nevertheless, the ataxic phenotype was neither improved nor delayed. Repeated s.c. ursodeoxycholic acid injections markedly elevated ursodeoxycholic acid levels in the brain without adverse effects, but provided no improvement in phenotype or cell survival in spinocerebellar ataxia type 1 mice.These results demonstrate that preserving neurons from degeneration is insufficient to prevent a behavioral phenotype in this transgenic model of polyglutamine disease. In addition, we suggest that the means by which creatine mitigates against the neurodegenerative effects of an ataxin-1 protein containing an expanded polyglutamine region is through mechanisms other than stabilization of mitochondrial membranes.