Genetic etiology of Fronto-Temporal Dementia

额颞叶痴呆的遗传病因学

• 批准号: 8335972
• 负责人: Bryan Traynor
• 金额: $ 20.95万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8335972
• 关键词: 9p21; Accounting; Affect; Aging; Alleles; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Atrophic; Autophagosome; Autopsy; Chromosomes; Clinical; Code; Data; Defect; Degradation Pathway; Dementia; Disease; Elderly; Epidemiology; Familial Amyotrophic Lateral Sclerosis; Family; Family Study; Finland; Frontotemporal Dementia; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Haplotypes; Impaired cognition; Incidence; Inclusion Bodies; Inherited; Laboratories; Linkage Disequilibrium; Location; Mediating; Motor Manifestations; Motor Neurons; Mutation; Myopathy; Neurodegenerative Disorders; Neurology; Neurons; Paget' s Disease; Paper; Pathogenesis; Patients; Phenotype; Population; Population Attributable Risks; Proteins; Publishing; Reporting; Research; Research Subjects; Risk; SOD1 gene; Screening procedure; Spinal Cord; Staging; Techniques; Temporal Lobe; Toxic effect; Ubiquitin; Ubiquitination; Work; age related; base; cohort; exome; frontal lobe; genetic variant; genome wide association study; genome-wide; motor neuron degeneration; mutant; neurogenetics; next generation; protein TDP-43; protein degradation; valosin-containing protein

During the last fiscal year, we have completed two projects that are directly relevant to unraveling the genetic causes of frontotemporal dementia (FTD). In the first project, we used exome sequencing to identify a coding mutation in the valosin-containing protein (VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis (ALS). This is directly relevant to FTD research, as mutations in VCP have previously been identified in families with Frontotemporal Dementia associated with Inclusion Body Myopathy and Pagets disease (IBMPFD). Screening of VCP in a cohort of 210 familial ALS cases and autopsy-proven ALS and ALS-FTD cases identified four additional mutations including a mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that VCP mutations may account for ∼1%-2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration, as well as frontal cortical regions. Furthermore, our work shows that it is possible to apply next generation sequencing techniques to successfully find causative genes in late-onset neurodegenerative diseases of aging, and provides further evidence that ALS and FTD share a common genetic etiology. This paper was published in Neuron in December 2010. In the second project, we published the results of our genome-wide association study of ALS (and ALS associated with FTD) in Finland. Finland is an ideal location for a genome-wide association study of these age-related neurodegenerative diseases because the incidence of this disease spectrum is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22, which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232kb block of linkage disequilibrium in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS, and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37.9% (95% CI 27.7-48.1) and that for D90A homozygosity was 25.5% (16.9-34.1). These data clearly show that the chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases. This paper was published in Lancet Neurology in October 2010. In summary, the current year has been successful in identifying genetic variants important in the pathogenesis of FTD using next generation sequencing and genome-wide association approaches. Our data also helps to unify FTD and ALS into a single disease rubic that encompasses two of the major late-onset neurodegenerative diseases. Each of the two studies employed large cohorts of research subjects, and utilized the sequencing and genotyping facilities available within the Laboratory of Neurogenetics, NIA.

在上一财政年度，我们完成了两个与揭示额颞叶痴呆（FTD）遗传原因直接相关的项目。在第一个项目中，我们使用外显子组测序在一个常染色体显性遗传肌萎缩性侧索硬化症（ALS）的意大利家庭中鉴定了含缬氨酸蛋白（VCP）基因的编码突变。这与FTD研究直接相关，因为VCP突变先前已在与包络体肌病和Pagets病（IBMPFD）相关的额颞叶痴呆家族中被发现。对210例家族性ALS病例和尸检证实的ALS和ALS- ftd病例进行VCP筛查，发现了4个额外的突变，包括一个病理证实的ALS病例中的突变。VCP蛋白对含泛素自噬体的成熟至关重要，突变型VCP的毒性部分是通过其对TDP-43蛋白的作用介导的，TDP-43蛋白是肌萎缩性侧索硬化神经病理学特征中泛素包涵体的主要成分。我们的数据扩大了IBMPFD的表型，包括运动神经元变性，表明VCP突变可能占家族性ALS的1%-2%，并提供了直接暗示运动神经元变性和额叶皮质区域泛素化/蛋白质降解途径缺陷的证据。此外，我们的工作表明，有可能应用下一代测序技术成功地找到迟发性衰老神经退行性疾病的致病基因，并进一步证明ALS和FTD具有共同的遗传病因。这篇论文发表在2010年12月的《神经元》杂志上。