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TMEM106b as a lysosomal adaptor to influence brain aging and tau pathogenesis

TMEM106b 作为溶酶体适配器影响大脑衰老和 tau 发病机制

基本信息

批准号：
10172237
负责人：
JOANNA L JANKOWSKY
金额：
$ 52.62万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10172237
关键词：
Adult Affect Age Aging Alleles Alzheimer&apos s Disease Amino Acids Amyotrophic Lateral Sclerosis Attention Biology Brain Catabolism Cell Nucleus Cells Cellular Stress Characteristics Code Cognitive Communities Consensus Sequence Data Set Dementia Disease Enzymes Frontotemporal Dementia Gene Expression Profile Genetic Transcription Half-Life Haplotypes Health Homeostasis Human Immunoprecipitation Impaired cognition In Vitro Integral Membrane Protein Knock-in Mouse Knock-out Knockout Mice Lead Link Linkage Disequilibrium Literature Lysosomes Maps Measures Mediating Modification Molecular Mus Nerve Degeneration Neurobehavioral Manifestations Neurons Nuclear Parkinson Disease Pathogenesis Pathology Phenocopy Post-Translational Protein Processing Property Protein Isoforms Proteins Proteomics Regulation Role Series Signal Transduction Site Stress Tauopathies Technology Testing Uncertainty Variant Vesicle Work aging brain base brain cell brain tissue case control cell motility cell type disorder risk genetic risk factor glycosylation hippocampal sclerosis human subject in vivo insight knock-down late endosome lens loss of function lysosomal proteins metabolomics nervous system disorder neuropathology overexpression preservation programs protein degradation resilience risk variant synergism tau Proteins tool transcriptome sequencing vacuolar H+-ATPase

项目摘要

Abstract TMEM106B first came to the attention of the neurodegeneration community as a modifier of disease risk in FTLD-TDP, where the protective haplotype was significantly less common in subjects than in healthy controls. Since this discovery, TMEM106B's protective influence has been extended to hippocampal sclerosis in aging, cognitive symptoms in ALS and PD, transcriptional indicators of brain aging, and functional resilience against neuropathological burden. Given its impact, we know surprisingly little about TMEM106B function. TMEM106B is localized to the late endosome and lysosome where past work suggests it regulates vesicle size and enzyme content, but has been much less definitive about its effect on lysosomal function. The protective TMEM106B haplotype is less transcriptionally active than the common (risk) variant and the only coding SNP identified appears to increase protein turnover, together suggesting that mild reduction of TMEM106B levels may be optimal for cognitive health. Based on past studies, we hypothesize that TMEM106B regulates lysosomal homeostasis through both local protein interactions at the lysosome and through nuclear signaling via TFEB. We further propose that this role becomes more critical with aging and disease, where lysosomal function must be maintained under cellular stress. As a platform for testing how TMEM106B levels or isoform impact lysosome composition and function in the healthy brain and under stress of aging or neuropathology, we have generated an allelic series of mice in which TMEM106B levels have been constitutively reduced, deleted, or substituted with a coding variant. In our first aim, we will test how TMEM106B levels affect lysosome pH, size, and catabolic function in the healthy brain and under conditions of aging and tauopathy. In our second aim, we will test whether TMEM106B influences lysosomal composition through local protein interactions, nuclear transcription, or both. In our final aim, we will test how the lone coding variant affects TMEM106B localization and lysosomal properties to determine whether this variant partially phenocopies TMEM106B loss of function. In each aim, we will leverage the technical capabilities of our Metabolomics and Proteomics Cores and the power of lysosomal immunoprecipitation to obtain an unbiased and up-close view of how lysosome composition and catabolism is influenced by TMEM106B. The role of TMEM106B has yet to be clarified and the existing literature is conflicted about its impact on the cell. But by tackling this protein in vivo under native expression conditions using the tools and technologies afforded by our Program, we have an unparalleled opportunity to conclusively determine how this protein influences lysosomal function in cells relevant to Alzheimer's disease and under conditions of aging and tauopathy that attend dementia. Ultimately, we hope that our work will offer mechanistic insight into the outsized influence held by this non-descript lysosomal protein across a growing swath of neurodegenerative conditions.

摘要