TRIM11 Prevents and Reverses Protein Aggregation and Rescues a Mouse Model of Parkinson’s Disease

• Published in: Cell reports (Cambridge) Vol. 33; no. 9; p. 108418
• Main Authors: Zhu, Guixin, Harischandra, Dilshan S., Ghaisas, Shivani, Zhang, Pengfei, Prall, Wil, Huang, Liangqian, Maghames, Chantal, Guo, Lili, Luna, Esteban, Mack, Korrie L., Torrente, Mariana P., Luk, Kelvin C., Shorter, James, Yang, Xiaolu
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2020; Elsevier
• Subjects: amyloid fibril; Animals; disaggregase; Disease Models, Animal; Humans; Mice; molecular chaperone; neurodegenerative diseases; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson’s disease; Protein Aggregates; protein aggregation; protein quality control; SUMO E3 ligase; TRIM proteins; TRIM11; Tripartite Motif Proteins - metabolism; Ubiquitin-Protein Ligases - metabolism; neurodegenerative diseases; molecular chaperone; disaggregase; protein aggregation; protein quality control; TRIM proteins; amyloid fibril; SUMO E3 ligase; TRIM11; Parkinson’s disease
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108418

Neurodegenerative diseases are characterized by the formation and propagation of protein aggregates, especially amyloid fibrils. However, what normally suppresses protein misfolding and aggregation in metazoan cells remains incompletely understood. Here, we show that TRIM11, a member of the metazoan tripartite motif (TRIM) family, both prevents the formation of protein aggregates and dissolves pre-existing protein deposits, including amyloid fibrils. These molecular chaperone and disaggregase activities are ATP independent. They enhance folding and solubility of normal proteins and cooperate with TRIM11 SUMO ligase activity to degrade aberrant proteins. TRIM11 abrogates α-synuclein fibrillization and restores viability in cell models of Parkinson’s disease (PD). Intracranial adeno-associated viral delivery of TRIM11 mitigates α-synuclein-mediated pathology, neurodegeneration, and motor impairments in a PD mouse model. Other TRIMs can also function as ATP-independent molecular chaperones and disaggregases. Thus, we define TRIMs as a potent and multifunctional protein quality-control system in metazoa, which might be applied to treat neurodegenerative diseases. [Display omitted] •TRIM11 prevents and reverses protein aggregation in an ATP-independent manner•These molecular chaperone and disaggregase activities enhance protein solubility•They also act together with TRIM11 SUMO ligase activity to degrade defective proteins•TRIM11 mitigates pathology, neurodegeneration, and motor defects in a mouse PD model Zhu at al. show that TRIM11 possesses ATP-independent molecular chaperone and disaggregase activities. These activities enhance the solubility of proteins and cooperate with TRIM11 SUMO ligase activity to degrade defective proteins. TRIM11 abrogates fibrillization of α-synuclein in vitro and in cells and rescues a mouse model of Parkinson’s disease.