Cdk5 suppression blocks SIRT1 degradation via the ubiquitin-proteasome pathway in Parkinson's disease models

• Published in: Biochimica et biophysica acta. General subjects Vol. 1862; no. 6; pp. 1443 - 1451
• Main Authors: Zhang, Qian, Zhang, Pei, Qi, Guang-Jian, Zhang, Zheng, He, Feng, Lv, Ze-Xi, Peng, Xiang, Cai, Hong-Wei, Li, Tong-Xia, Wang, Xue-Min, Tian, Bo
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2018
• Subjects: Alzheimer disease; amyotrophic lateral sclerosis; animal models; Animals; Behavior, Animal; cell lines; Cells, Cultured; cyclin-dependent kinase; Cyclin-Dependent Kinase 5 - genetics; Cyclin-Dependent Kinase 5 - metabolism; Degradation; disease models; Disease Models, Animal; environmental factors; gene overexpression; genetic factors; Humans; Male; Mice; Mice, Inbred C57BL; neurons; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents; neuroprotective effect; neurotoxins; Parkinson disease; Parkinson Disease - etiology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Proteasome Endopeptidase Complex - genetics; Proteasome Endopeptidase Complex - metabolism; protein synthesis; Rats, Sprague-Dawley; SIRT1; Sirtuin 1 - physiology; transgenic animals; Ubiquitin-proteasome pathway; Ubiquitins - metabolism; Degradation; Parkinson's disease; SIRT1; Ubiquitin-proteasome pathway
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2018.03.021

The NAD+-dependent protein deacetylase sirtuin 1 (SIRT1), a member of the sirtuin family, may have a neuroprotective effect in multiple neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). Many studies have suggested that overexpression-induced or resveratrol-treated activation of SIRT1 could significantly ameliorate several neurodegenerative diseases in mouse models. However, the type of SIRT1, protein expression levels and underlying mechanisms remain unclear, especially in PD. In this study, the results demonstrated that SIRT1 knockout markedly worsened the movement function in MPTP-lesioned animal model of PD. SIRT1 expression was found to be markedly decreased not only in environmental factor PD models, neurotoxin MPP+-treated primary culture neurons and MPTP-induced mice but also in genetic factor PD models, overexpressed α-synuclein-A30PA53T SH-SY5Y stable cell line and hm2α-SYN-39 transgenic mouse strain. Importantly, the degradation of SIRT1 during MPP+ treatment was mediated by the ubiquitin-proteasome pathway. Furthermore, the results indicated that cyclin-dependent kinase 5 (Cdk5) was also involved in the decrease of SIRT1 expression, which could be efficiently blocked by the inhibition of Cdk5. In conclusion, our findings revealed that the Cdk5-dependent ubiquitin-proteasome pathway mediated degradation of SIRT1 plays a vital role in the progression of PD. •SIRT1 knockout aggravates the motor behavior phenotype in PD models.•SIRT1 expression was decreased in cellular and animal models of PD.•Degradation of SIRT1 was mediated by the ubiquitin-proteasome system.•Cdk5 was involved in the decrease of SIRT1 expression.