权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Endolysosomal trafficking and lipid metabolism defects in FTLD

FTLD 中的内溶酶体运输和脂质代谢缺陷

基本信息

批准号：
10645964
负责人：
Eric J Huang
金额：
$ 67.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2023-05-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10645964
关键词：
3-Dimensional Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Astrocytes Automobile Driving Autophagocytosis Autopsy Biochemical Cell Fractionation Coculture Techniques Complement Complement Activation Data Defect Disease Endosomes Frontotemporal Lobar Degenerations GRN gene Human Image Inflammatory Knock-in Mouse Knock-out Knockout Mice Label Lipids Lysosomes Mediating Memory impairment Microglia Mus Mutation Nature Nerve Degeneration Neurons Organoids PGRN gene Pathology Pathway interactions Patients Phenotype Phospholipids Production Property Proteomics RNA-Binding Proteins Role Single Nucleotide Polymorphism TDP-43 aggregation Testing Tissues Toxic effect Validation Vesicle Work age related aging brain astrogliosis brain tissue cohort comparative cytokine dominant genetic mutation induced pluripotent stem cell limbic-predominant age-related TDP-43 encephalopathy lipid metabolism lipid transport lipidomics mouse model mutant neural circuit neuroinflammation neuron loss neurotoxic neurotoxicity new therapeutic target protein TDP-43 single nucleus RNA-sequencing trafficking transcriptome

项目摘要

PROJECT SUMMARY Dominant mutations in the human GRN gene cause haploinsufficiency in Progranulin (PGRN) protein levels and are a leading cause of frontotemporal lobar degeneration with aggregation of RNA binding protein TDP-43 (FTLD-TDP). In addition, single nucleotide polymorphism (SNP) in GRN has been identified as a risk factor for AD and Limbic predominant, Age-related TDP-43 Encephalopathy (LATE), a major cause of memory impairments in patients over 90 years old. Despite the critical role of PGRN in brain aging, however, the exact mechanism by which PGRN haploinsufficiency promotes neurodegeneration remains poorly understood. By analyzing aging cohorts of Grn knockout (Grn-/-) and humanized GrnR493X/R493X knockin mice, we have shown that PGRN-deficient microglia produce more complement proteins and pro-inflammatory cytokines to promote neuronal cell death and TDP-43 proteinopathy during brain aging. Interestingly, our ongoing work shows that blocking complement activation and proinflammatory cytokines TNFa and IL-1a does not completely mitigate neurodegeneration, but rather uncover late-onset microglial pathology characterized by profound accumulation of lipids in Grn-/-, Grn-/-;C1qa-/-;C3-/-, and Grn-/-;C1qa-/-;Tnf-/-;Il1a-/- microglia. Using lipidomics and subcellular fractionation, we further show that loss of PGRN causes severe blockade in the endolysosomal trafficking of lipids in Grn-/- microglia, which interferes with lysosome-mediated degradation of lipid droplets and increased production of proinflammatory oxidized phospholipids. Together, our results broach the hypothesis that PGRN deficiency causes profound endolysosomal trafficking defects of lipids in microglia and astrocytes to promote neuronal vulnerability in neurodegeneration. To test this hypothesis, we propose to (1) delineate the mechanism of endolysosomal trafficking and secretory autophagy that promote lipid-mediated toxicity in Grn-/- microglia, (2) characterize the role of lipid-dependent and -independent mechanisms in promoting neurotoxicity in Grn-/- astrocytes, and (3) delineate the contributions of lipids to glial toxicity in FTLD-GRN using comparative snRNA- seq, IPSC-derived organoids and postmortem tissues. The proposed parallel human-mouse studies will uncover the contributions of lipid-mediated toxicity in highly disease vulnerable regions in Grn-/- mice and FTLD-GRN will uncover critical mechanisms that promote glial pathology and neurodegeneration during brain aging and lead to novel therapeutic targets for ADRD.

项目总结