Investigating the role of TMEM106b genetics and pathology in Alzheimer’s disease, LATE and FTLD

研究 TMEM106b 遗传学和病理学在阿尔茨海默病、LATE 和 FTLD 中的作用

• 批准号: 10806465
• 负责人: Keith A Josephs
• 金额: $ 109.71万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10806465
• 关键词: Affect; Alleles; Alzheimer' s Disease; Amygdaloid structure; Amyotrophic Lateral Sclerosis; Antibodies; Autopsy; Biochemical; Biology; Brain; C9ORF72; Cell physiology; Characteristics; Clinical; Code; Cognition; Cryoelectron Microscopy; Data; Data Set; Deposition; Disease; Disease Outcome; Exhibits; Filament; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Gene Cluster; Genetic; Genetic Variation; Genotype; Glucose; Haplotypes; Heterogeneity; Hippocampus; Histologic; Impaired cognition; Individual; Induced pluripotent stem cell derived neurons; Integral Membrane Protein; Link; Linkage Disequilibrium; Lysosomes; Mass Spectrum Analysis; Measures; Metabolic; Metabolism; Methods; Mutation; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Outcome; PGRN gene; Pathogenicity; Pathologic; Pathology; Pathway Analysis; Patients; Pattern; Post-Translational Protein Processing; Proteins; Proteomics; Regulation; Reporting; Resistance; Risk; Role; Serine; Single Nucleotide Polymorphism; Structure; TDP-43 aggregation; Tauopathies; Techniques; Testing; Threonine; Untranslated RNA; Variant; Work; comparative; disorder risk; experimental study; fluorodeoxyglucose positron emission tomography; frontal lobe; genetic variant; human tissue; improved; limbic-predominant age-related TDP-43 encephalopathy; neuroimaging; neuropathology; normal aging; novel; protective allele; protein TDP-43; protein protein interaction; risk variant; sarkosyl; synucleinopathy

PROJECT SUMMARY/ABSTRACT Filaments derived from transmembrane protein 106B (TMEM106B) were recently discovered to represent a novel pathological hallmark in a range of neurodegenerative disorders, including TDP-43 proteinopathies, synucleinopathies, and tauopathies. Notably, TMEM106B genetic variants are linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), particularly cases with progranulin (GRN) and chromosome 9 open reading frame 72 (C9ORF72) mutations, and limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathologic change. TMEM106B variants also associate with cognitive decline in patients with amyotrophic lateral sclerosis. While several single nucleotide polymorphisms (SNPs) in TMEM106B have been identified and linked to disease risk, only one (rs3173615) introduces a coding change (p.T185S) and it is in high linkage disequilibrium with other risk SNPs. To investigate the intriguing idea that rs3173615 could modulate disease risk through regulation of TMEM106B deposition, we developed an antibody against the TMEM106B filament core sequence. Consistent with recent reports, we detected TMEM106B-positive filaments in the sarkosyl-insoluble fraction from FTLD-TDP and LATE patients. Remarkably, we also observed increased accumulation of insoluble TMEM106B in FTLD-TDP patients homozygous for the rs3173615 risk allele (encoding threonine at residue 185 instead of serine). Collectively, these findings support the hypothesis that TMEM106B aggregation explains the link between genetic variation at the TMEM106B locus and disease risk – and we suspect that it could also explain potential links between rs3173615, TDP-43 proteinopathy, and cognitive decline. We also speculate that differences in TMEM106B accumulation contribute to clinical and pathologic heterogeneity in both FTLD and LATE. Moreover, given that LATE is associated with greater hypometabolism on [18F] fluorodeoxyglucose PET (FDG-PET) in the frontal lobe, a region populated by TMEM106B fibrils, we predict that rs3173615 genotype will also associate with neuroimaging measures of neurodegeneration. In this project, we will investigate the impact of rs3173615 genotype on TMEM106B aggregation and assess whether it associates with TDP-43 proteinopathy and clinical outcomes. We will also explore the mechanism by which the rs3173615 coding variant affects TMEM106B fibril formation, as well as the potential functional consequences of TMEM106B genetic variation and fibril accumulation. Our approach to the latter will be two-fold: as a candidate-based approach, we will determine whether TMEM106B genetic variants impact lysosomal function in neurons, and as an unbiased approach, we will use proteomic analyses to build protein-protein interaction and co-aggregation networks from the soluble and insoluble fractions of patient brains, focusing on differences observed in carriers of the T185 allele versus carriers of the S185 protective genotype.

项目概要/摘要 最近发现源自跨膜蛋白 106B (TMEM106B) 的丝代表 一系列神经退行性疾病的新病理标志，包括 TDP-43 蛋白病， 突触核蛋白病和 tau 蛋白病。值得注意的是，TMEM106B 基因变异与额颞部疾病的风险相关 伴有 TDP-43 包涵体的脑叶变性 (FTLD-TDP)，特别是伴有颗粒体蛋白前体 (GRN) 和 9 号染色体开放阅读框 72 (C9ORF72) 突变和边缘主导的年龄相关 TDP-43 脑病（晚期）神经病理改变。 TMEM106B 变异也与认知能力下降有关 肌萎缩侧索硬化症患者。虽然一些单核苷酸多态性（SNP） TMEM106B 已被识别并与疾病风险相关，只有一个 (rs3173615) 引入了编码更改 (p.T185S)并且它与其他风险SNP处于高度连锁不平衡。为了研究这个有趣的想法 rs3173615 可以通过调节 TMEM106B 沉积来调节疾病风险，我们开发了一种 针对 TMEM106B 丝核心序列的抗体。与最近的报告一致，我们发现 FTLD-TDP 和 LATE 患者的肌氨酰不溶部分中的 TMEM106B 阳性细丝。 值得注意的是，我们还观察到 FTLD-TDP 患者中不溶性 TMEM106B 的积累增加 rs3173615 风险等位基因纯合（在残基 185 处编码苏氨酸而不是丝氨酸）。总的来说， 这些发现支持这样的假设：TMEM106B 聚集解释了遗传变异之间的联系 TMEM106B 位点和疾病风险 - 我们怀疑它也可以解释之间的潜在联系 rs3173615、TDP-43 蛋白病和认知能力下降。我们还推测 TMEM106B 的差异 积累导致 FTLD 和 LATE 的临床和病理异质性。此外，鉴于 LATE 与额叶 [18F] 氟脱氧葡萄糖 PET (FDG-PET) 代谢减退程度相关 叶，一个由 TMEM106B 原纤维填充的区域，我们预测 rs3173615 基因型也将与 神经变性的神经影像学测量。在这个项目中，我们将调查 rs3173615 的影响 TMEM106B 聚集的基因型并评估其是否与 TDP-43 蛋白病和临床相关 结果。我们还将探讨 rs3173615 编码变体影响 TMEM106B 原纤维的机制 形成，以及 TMEM106B 遗传变异和原纤维的潜在功能后果 积累。我们对后者的方法将有两个方面：作为基于候选人的方法，我们将确定 TMEM106B 遗传变异是否影响神经元的溶酶体功能，作为一种公正的方法，我们 将使用蛋白质组学分析从可溶性蛋白质中构建蛋白质-蛋白质相互作用和共聚集网络 以及患者大脑的不溶部分，重点关注 T185 等位基因携带者与 T185 等位基因携带者中观察到的差异 S185保护性基因型携带者。