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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目摘要/摘要最近发现源自跨膜蛋白106b（TMEM106B）的细丝代表在包括TDP-43蛋白质在内的一系列神经退行性疾病中的新病理标志，剧核病和tauopathies。值得注意的是，TMEM106B遗传变异与额颞的风险有关带有TDP-43夹杂物（FTLD-TDP）的Lobar变性，尤其是程序Nulin（GRN）和染色体9开放式阅读框72（C9orf72）突变和与年龄有关的TDP-43 脑病（晚期）神经病理学变化。 TMEM106B变体也与认知能力下降有关肌萎缩性侧索硬化症患者。而几个单核苷酸多态性（SNP） TMEM106B已被识别并与疾病风险有关，只有一个（RS3173615）引入了编码更改（P.T185S），并且与其他风险SNP处于高连接阶段。调查有趣的想法 RS3173615可以通过调节TMEM106B沉积来调节疾病的风险，我们开发了一个针对TMEM106B细丝核序列的抗体。与最近的报告一致，我们检测到 FTLD-TDP和晚患者的sarkosyl-solusoluble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的纯合风险等位基因（在185居住地编码苏氨酸而不是丝氨酸）。共同这些发现支持TMEM106B聚集解释遗传变异之间的联系的假设在TMEM106B基因座和疾病风险上 - 我们怀疑它也可以解释 RS3173615，TDP-43蛋白质病和认知能力下降。我们还推测TMEM106B的差异积累有助于FTLD和晚期的临床和病理异质性。而且，鉴于这一点迟到与额叶中[18F]氟脱氧葡萄糖PET（FDG-PET）上的较大的低代谢有关 Lobe是由TMEM106B原纤维填充的区域，我们预测RS3173615基因型也将与神经退行性的神经影像学指标。在这个项目中，我们将研究RS3173615的影响 TMEM106B聚集和评估的基因型是否与TDP-43蛋白质病和临床相关结果。我们还将探索RS3173615编码变体的机制影响TMEM106B Fibril TMEM106B遗传变异和原纤维的形成以及潜在的功能后果积累。我们以后采用的方法将是两个方面：作为一种基于候选的方法，我们将确定 TMEM106B遗传变异是否影响神经元中的溶酶体功能，并且作为一种公正的方法，我们将使用蛋白质组学分析来构建可溶性的蛋白质 - 蛋白质相互作用和共聚集网络患者大脑的不溶性部分，重点是在T185等位基因的载体中观察到的差异 S185保护基因型的载体。