TRIM11 protects against tauopathies and is down-regulated in Alzheimer's disease

• 成果类型: Article
• 署名作者: Zhang, Zi-Yang; Harischandra, Dilshan S.; Wang, Ruifang; Ghaisas, Shivani; Zhao, Janet Y.; McMonagle, Thomas P.; Zhu, Guixin; Lacuarta, Kenzo D.; Song, Jianing; Trojanowski, John Q.; Xu, Hong; Lee, Virginia M. Y.; Yang, Xiaolu
• 署名单位: University of Pennsylvania; University of Pennsylvania; Northwestern University; Zhejiang University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8426
• DOI: 10.1126/science.add6696
• 发表日期: 2023-07-28
• 页码: 413-+
• 关键词: neurofibrillary tangles; amyloid-beta; misfolded proteins; receptor trim21; senile plaques; synthetic tau; gene; pathology; SYSTEM; hsp70

摘要

Aggregation of tau into filamentous inclusions underlies Alzheimer's disease (AD) and numerous other neurodegenerative tauopathies. The pathogenesis of tauopathies remains unclear, which impedes the development of disease-modifying treatments. Here, by systematically analyzing human tripartite motif (TRIM) proteins, we identified a few TRIMs that could potently inhibit tau aggregation. Among them, TRIM11 was markedly down-regulated in AD brains. TRIM11 promoted the proteasomal degradation of mutant tau as well as superfluous normal tau. It also enhanced tau solubility by acting as both a molecular chaperone to prevent tau misfolding and a disaggregase to dissolve preformed tau fibrils. TRIM11 maintained the connectivity and viability of neurons. Intracranial delivery of TRIM11 through adeno-associated viruses ameliorated pathology, neuroinflammation, and cognitive impairments in multiple animal models of tauopathies. These results suggest that TRIM11 down-regulation contributes to the pathogenesis of tauopathies and that restoring TRIM11 expression may represent an effective therapeutic strategy.