期刊
ACTA NEUROPATHOLOGICA
卷 143, 期 1, 页码 33-53出版社
SPRINGER
DOI: 10.1007/s00401-021-02379-z
关键词
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资金
- Rainwater Charitable Foundation [IMSSM: R01 AG054008, R01 NS095252, R01 AG060961, R01 NS086736]
- Genentech/Roche
- Alexander Saint-Amand Fellowship (JFC) [F32 AG056098, P50 AG005138, P30 AG066514, 75N95019C00049, K99 AG070109, U01 AG058635]
- Arizona Department of Health Services [U24 NS072026, P30 AG019610]
- Michael J. Fox Foundation for Parkinson's Research
- Johns Hopkins [P50 AG05146]
- U Iowa [K23 NS109284]
- Roy J. Carver Foundation
- Carver College of Medicine
- Williams-Cannon Foundation (MMH), Northwestern [P30 AG013854]
- Emory [P30 NS055077, P50 AG025688]
- OHSU [P30 AG08017]
- UTSW: Winspear Family Center for Research on the Neuropathology of Alzheimer Disease (CWIII)
- Toronto: Rossy Foundation
- Safra Foundation (GGK)
- Stanford [R01AG059848]
- MADRC [P50 AG05134, P30 AG062421]
- RUSH [AG10161]
- MAP
- UCI [R01AG021055, P50AG016573, P01AG000538]
- UCSD [P30 AG062429 01, P50 AG005131]
- UK [P30 AG028383]
- U Washington [P50 AG005136, P30 AG066509, U01 AG006781, U19 066567]
- Nancy and Buster Alvord Endowment
- Washington U/Knight ADRC [P30 AG066444, P01 AG003991, 01 AG026276]
- Newcastle: UK Medical Research Council [G0400074]
- Brains for Dementia research
- Alzheimer's Society
- Alzheimer's Research UK
- NIHR Newcastle Biomedical Research Centre
- Newcastle University
- J.M.R. Barker Foundation
- McCune Foundation
- BU/MSSM/MAYO [R01 AG062348]
- UMC [P50AG008702]
- BU [U54 NS115266, R01 CA079830]
- UPENN [30 AG010124, P01 AG017586, U19 AG062418, P30 AG072979, P01 AG066597, R01 AG066152]
- PITT [R01 AG066152 P30 AG066468]
- MRC [G0400074] Funding Source: UKRI
The study found that Primary age-related tauopathy (PART) has a genetic architecture that partially overlaps with Alzheimer's disease (AD) and other tauopathies, and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.
Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-beta (A beta) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from A beta toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.
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