Melatonin attenuates MPTP-induced neurotoxicity via preventing CDK5-mediated autophagy and SNCA/α-synuclein aggregation

Abstract

Keywords: autophagy, CDK5, melatonin, MPTP, SNCA, TH Abbreviations: ATG7, autophagy-related 7; BAFA1, bafilomycin A 1 ; CDK5, cyclin-dependent kinase 5; CDK5R1/p35/p25, cyclindependent kinase 5, regulatory subunit 1 (p35); DA, dopamine; DAPI, 4 0 ,6-diamidino-2-phenylindole; i.p, intraperitoneally; s.c, subcutaneously; ICV, intracerebroventricular; MAP1LC3B/LC3B, microtubule-associated protein 1 light chain 3 b; MAP2, microtube-associated protein 2; MPTP, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine; PD, Parkinson disease; PEBP1, phosphatidylethanolamine binding protein 1; PI, propidium iodide; SNc, substantia nigra pars compacta; SNCA/a-synuclein, synuclein, a (non A4 component of amyloid precursor); TH, tyrosine hydroxylase.Autophagy is involved in the pathogenesis of neurodegenerative diseases including Parkinson disease (PD). However, little is known about the regulation of autophagy in neurodegenerative process. In this study, we characterized aberrant activation of autophagy induced by neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and demonstrated that melatonin has a protective effect on neurotoxicity. We found an excessive activation of autophagy in monkey brain tissues and C6 cells, induced by MPTP, which is mediated by CDK5 (cyclin-dependent kinase 5). MPTP treatment significantly reduced total dendritic length and dendritic complexity of cultured primary cortical neurons and melatonin could reverse this effect. Decreased TH (tyrosine hydroxylase)-positive cells and dendrites of dopaminergic neurons in the substantia nigra pars compacta (SNc) were observed in MPTP-treated monkeys and mice. Along with decreased TH protein level, we observed an upregulation of CDK5 and enhanced autophagic activity in the striatum of mice with MPTP injection. These changes could be salvaged by melatonin treatment or knockdown of CDK5. Importantly, melatonin or knockdown of CDK5 reduced MPTP-induced SNCA/ a-synuclein aggregation in mice, which is widely thought to trigger the pathogenesis of PD. Finally, melatonin or knockdown of CDK5 counteracted the PD phenotype in mice induced by MPTP. Our findings uncover a potent role of CDK5-mediated autophagy in the pathogenesis of PD, and suggest that control of autophagic pathways may provide an important clue for exploring potential target for novel therapeutics of PD.

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

“…Many types of research showed that the high metal ions could aggravate the formation of α-syn fibrillation and aggregation, result in the cell injury and consequently contribute to the progressive of PD [7,[102][103][104][105][106]. And MPTP, a well-known neurotoxin, is also associated with the aggregation of α-syn, which was confirmed by a study that the oligomers of SNCA (51 kD) increased in the SNpc of monkeys administrated intravenously with MPTP (0.3 mg/kg) twice a week for three months [107]. Moreover, there are other environmental factors including solvents and nanoparticles that have been proved to be associated with α-syn aggregation.…”

Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux

“…Although during the last decade different studies have related melatonin with autophagy regulation in different disease models, like cardiac and brain ischemia or subarachnoid hemorrhage, kainic acid–induced toxicity, prion peptide–induced toxicity, Parkinson's disease, traumatic brain injury, or aging models, little is known about its implication in AD, and more specifically in tauopathies. Melatonin is widely known to regulate the autophagy‐lysosome machinery at very different levels .…”

Melatonin attenuates traumatic brain injury‐induced inflammation: a possible role for mitophagy

“…However, the precise mechanism by which melatonin inhibits phosphorylation of mTOR Ser2448 remains poorly unknown. In other models, melatonin also modulates autophagy via cyclin‐dependent kinase 5‐mediated pathway or sirtuin 3‐dependent pathway .…”