2. Academic Validation
  3. The contribution of proteasomal impairment to autophagy activation by C9orf72 poly-GA aggregates

The contribution of proteasomal impairment to autophagy activation by C9orf72 poly-GA aggregates

  • Cell Mol Life Sci. 2022 Aug 29;79(9):501. doi: 10.1007/s00018-022-04518-5.
Mei Pu 1 2 3,  Yusi Tai 1 3,  Luyang Yuan 4,  Yu Zhang 5,  Huijie Guo 1 2 3,  Zongbing Hao 6,  Jing Chen 1,  Xinming Qi 1,  Guanghui Wang 7,  Zhouteng Tao 8 9,  Jin Ren 10 11 12 13
Affiliations

Affiliations

  • 1 Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 3 University of Chinese Academy of Sciences, Beijing, China.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.
  • 5 Key Laboratory of Receptor Research, Department of Neuropharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 6 Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
  • 7 Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China. wanggh@suda.edu.cn.
  • 8 Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China. taozhouteng@simm.ac.cn.
  • 9 State Key Laboratory of Transient Optics and Photonics, Xi'an Institute of Optics and Precision Mechanics, Chinese Academy of Sciences, Xi'an, China. taozhouteng@simm.ac.cn.
  • 10 Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, China. jren@cdser.simm.ac.cn.
  • 11 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. jren@cdser.simm.ac.cn.
  • 12 University of Chinese Academy of Sciences, Beijing, China. jren@cdser.simm.ac.cn.
  • 13 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. jren@cdser.simm.ac.cn.
PMID: 36036324 DOI: 10.1007/s00018-022-04518-5
Abstract

Background: Poly-GA, a dipeptide repeat protein unconventionally translated from GGGGCC (G4C2) repeat expansions in C9orf72, is abundant in C9orf72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9orf72-ALS/FTD). Although the poly-GA aggregates have been identified in C9orf72-ALS/FTD neurons, the effects on UPS (ubiquitin-proteasome system) and Autophagy and their exact molecular mechanisms have not been fully elucidated.

Results: Herein, our in vivo experiments indicate that the mice expressing ploy-GA with 150 repeats instead of 30 repeats exhibit significant aggregates in cells. Mice expressing 150 repeats ploy-GA shows behavioral deficits and activates Autophagy in the brain. In vitro findings suggest that the poly-GA aggregates influence proteasomal by directly binding Proteasome subunit PSMD2. Subsequently, the poly-GA aggregates activate phosphorylation and ubiquitination of p62 to recruit autophagosomes. Ultimately, the poly-GA aggregates lead to compensatory activation of Autophagy. In vivo studies further reveal that rapamycin (Autophagy activator) treatment significantly improves the degenerative symptoms and alleviates neuronal injury in mice expressing 150 repeats poly-GA. Meanwhile, rapamycin administration to mice expressing 150 repeats poly-GA reduces neuroinflammation and aggregates in the brain.

Conclusion: In summary, we elucidate the relationship between poly-GA in the Proteasome and autophagy: when poly-GA forms complexes with the Proteasome, it recruits autophagosomes and affects Proteasome function. Our study provides support for further promoting the comprehension of the pathogenesis of C9orf72, which may bring a hint for the exploration of rapamycin for the treatment of ALS/FTD.

Keywords

ALS; Autophagy; C9orf72; Poly-GA; Proteasome.

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