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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.

项目总结/文摘