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

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.

CDK5-mediated phosphorylation of Sirt2 contributes to depressive-like behavior induced by social defeat stress.

Major depressive disorder (MDD) is a common, severe and recurrent psychiatric disorder worldwide; however, the underlying neuropathological mechanisms remain elusive. Histone deacetylases (HDACs) appear to play an essential role in depression. As the class III HDACs, Sirt1 and Sirt2 have attracted the most interest in the nervous system. Indeed, chronic stress decreased Sirt1 activity and down-regulated Sirt1 gene expression in MDD. Nevertheless, there is a paucity of literature on the role of Sirt2. To study the role of Sirt2 we established a MDD mouse model in wild type and Sirt2 knockout C57BL/6 mice using social defeat stress (SDS). We found that a lack of Sirt2 blocked the development of SDS-induced depressive-like behavior. Moreover, SDS led to Sirt2 phosphorylation in the amygdala without changing total Sirt2 levels, and blocking the phosphorylation of Sirt2 by CDK5 at serine residues 368 and 372 prevented SDS-induced depressive-like behavior and Sirt2 nuclear import. We also discovered that SDS-induced Sirt2 phosphorylation was involved in VTA-amygdala modulation using TetTag-pharmacogenetic method. These results suggest that CDK5 mediates phosphorylation of Sirt2 in the amygdala and contributes to the depressive-like behavior induced by SDS. This study highlights that inhibiting CDK5-dependent phosphorylation of Sirt2 at serine residues 368 and 372 by myristoylated membrane-permeabilising peptide (Sirt2-p), rather than using non-specific sirtuin inhibitors, may be a novel strategy for treating depression.

CDK5-mediated phosphorylation of XBP1s contributes to its nuclear translocation and activation in MPP+-induced Parkinson's disease model.

Parkinson's disease (PD) is an irreversible and progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta. Growing evidence indicates that endoplasmic reticulum stress is a hallmark of PD; however, its exact contribution to the disease process remains poorly understood. Here, we used molecular biology methods and RNA-Seq analysis to explored an unexpected role of spliced X-Box binding protein 1 (XBP1s) in the nervous system. In this study, we determined that the IRE1α/XBP1 pathway is activated in MPP+-treated neurons. Furthermore, XBP1s was identified as a substrate of CDK5 and that the phosphorylation of XBP1s at the Ser61 residue enhances its nuclear migration, whereas mutation of the residue to alanine substantially reduces its nuclear translocation and activity. Importantly, phosphorylated XBP1s acts as a nuclear transcription factor for multiple target genes, including metabolic-related genes, FosB, and non-coding RNAs. Our findings confirm that the IRE1α/XBP1 pathway is activated in PD, and reveal a novel role of XBP1s in the pathogenesis of PD. This pathway may be a new therapeutic strategy for PD.