SIRT5-Mediated Desuccinylation of RAB7A Protects Against Cadmium-Induced Alzheimer's Disease-Like Pathology by Restoring Autophagic Flux

  • Adv Sci (Weinh). 2024 Jun 5:e2402030. doi: 10.1002/advs.202402030.
Ping Deng  1 ,  Tengfei Fan  2 ,  Peng Gao  1 ,  Yongchun Peng  2 ,  Min Li  3  4 ,  Jingdian Li  1 ,  Mingke Qin  1 ,  Rongrong Hao  1 ,  Liting Wang  5 ,  Min Li  1 ,  Lei Zhang  1 ,  Chunhai Chen  1 ,  Mindi He  1 ,  Yonghui Lu  1 ,  Qinlong Ma  1 ,  Yan Luo  1 ,  Li Tian  1 ,  Jia Xie  1 ,  Mengyan Chen  1 ,  Shangcheng Xu  6 ,  Zhou Zhou  7 ,  Zhengping Yu  1 ,  Huifeng Pi  1  8
Affiliations
  • 1. Department of Occupational Health (Key Laboratory of Electromagnetic Radiation Protection, Ministry of Education), Army Medical University (Third Military Medical University), Chongqing, 400038, China.
  • 2. Department of Oral and Maxillofacial Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410007, China.
  • 3. Basic Medical Laboratory, General Hospital of Central Theater Command, Wuhan, 430070, China.
  • 4. Hubei Key Laboratory of Central Nervous System Tumour and Intervention, Wuhan, 430070, China.
  • 5. Biomedical Analysis Center, Army Medical University, Chongqing, 400038, China.
  • 6. Center of Laboratory Medicine, Chongqing Prevention and Treatment Center for Occupational Diseases, Chongqing Key Laboratory of Prevention and Treatment for Occupational Diseases and Poisoning, Chongqing, 400060, China.
  • 7. Center for Neuro Intelligence, School of Medicine, Chongqing University, Chongqing, 400030, China.
  • 8. State Key Laboratory of Trauma and Chemical Poisoning, Army Medical University, Chongqing, 400038, China.
PMID: 38837686 DOI: 10.1002/advs.202402030
Abstract

Cadmium (Cd) is a neurotoxic contaminant that induces cognitive decline similar to that observed in Alzheimer's disease (AD). Autophagic flux dysfunction is attributed to the pathogenesis of AD, and this study aimed to investigate the effect of Autophagy on environmental Cd-induced AD progression and the underlying mechanism. Here, Cd exposure inhibited autophagosome-lysosome fusion and impaired lysosomal function, leading to defects in autophagic clearance and then to APP accumulation and nerve cell death. Proteomic analysis coupled with Ingenuity Pathway Analysis (IPA) identified SIRT5 as an essential molecular target in Cd-impaired autophagic flux. Mechanistically, Cd exposure hampered the expression of SIRT5, thus increasing the succinylation of RAB7A at lysine 31 and inhibiting RAB7A activity, which contributed to autophagic flux blockade. Importantly, SIRT5 overexpression led to the restoration of autophagic flux blockade, the alleviation of Aβ deposition and memory deficits, and the desuccinylation of RAB7A in Cd-exposed FAD4T mice. Additionally, SIRT5 levels decrease mainly in neurons but not in Other cell clusters in the brains of AD patients according to single-nucleus RNA Sequencing data from the public dataset GSE188545. This study reveals that SIRT5-catalysed RAB7A desuccinylation is an essential adaptive mechanism for the amelioration of Cd-induced autophagic flux blockade and AD-like pathogenesis.

Keywords
alzheimer's disease; autophagy; cadmium; rab7a; sirt5.
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