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

Science (New York, N.Y.) 2023 Jul 28

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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.

Citation

Zi-Yang Zhang, Dilshan S Harischandra, Ruifang Wang, Shivani Ghaisas, Janet Y Zhao, Thomas P McMonagle, Guixin Zhu, Kenzo D Lacuarta, Jianing Song, John Q Trojanowski, Hong Xu, Virginia M-Y Lee, Xiaolu Yang. TRIM11 protects against tauopathies and is down-regulated in Alzheimer's disease. Science (New York, N.Y.). 2023 Jul 28;381(6656):eadd6696