Abstract
BACKGROUND: Parkinson's disease (PD) is the second most frequent age-related neurodegenerative disorder and is characterized by the loss of dopaminergic neurons. Both environmental and genetic aspects are involved in the pathogenesis of PD. Osmotin is a structural and functional homolog of adiponectin, which regulates the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) via adiponectin receptor 1 (AdipoR1), thus attenuating PD-associated pathology. Therefore, the current study investigated the neuroprotective effects of osmotin using in vitro and in vivo models of PD. METHODS: The study used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced and neuron-specific enolase promoter human alpha-synuclein (NSE-haSyn) transgenic mouse models and 1-methyl-4-phenylpyridinium (MPP )- or alpha-synuclein A53T-treated cell models. MPTP was injected at a dose of 30 mg/kg/day for five days, and osmotin was injected twice a week at a dose of 15 mg/kg for five weeks. We performed behavioral tests and analyzed the biochemical and molecular changes in the substantia nigra pars compacta (SNpc) and the striatum. RESULTS: Based on our study, osmotin mitigated MPTP- and a-synuclein-induced motor dysfunction by upregulating the nuclear receptor-related 1 protein (Nurr1) transcription factor and its downstream markers tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT2). From a pathological perspective, osmotin ameliorated neuronal cell death and neuroinflammation by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Additionally, osmotin alleviated the accumulation of a-synuclein by promoting the AMPK/mammalian target of rapamycin (mTOR) autophagy signaling pathway. Finally, in nonmotor symptoms of PD, such as cognitive deficits, osmotin restored synaptic deficits, thereby improving cognitive impairment in MPTP- and a-synuclein-induced mice. CONCLUSIONS: Therefore, our findings indicated that osmotin significantly rescued MPTP/a-synuclein-mediated PD neuropathology. Altogether, these results suggest that osmotin has potential neuroprotective effects in PD neuropathology and may provide opportunities to develop novel therapeutic interventions for the treatment of PD.
Original language | English |
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Article number | 66 |
Number of pages | 15 |
Journal | Journal of biomedical science |
Volume | 30 |
Issue number | 1 |
DOIs | |
Publication status | Published - 11 Aug 2023 |
Keywords
- Dopaminergic neuron
- Neuroinflammation
- Osmotin
- Parkinson’s disease
- a-Synuclein
- Humans
- Mice
- Animals
- Parkinson Disease/metabolism
- alpha-Synuclein/genetics metabolism pharmacology
- Neuroprotective Agents/pharmacology
- AMP-Activated Protein Kinases/metabolism
- Substantia Nigra/metabolism
- Signal Transduction
- Dopaminergic Neurons/metabolism
- TOR Serine-Threonine Kinases/genetics metabolism pharmacology
- Mice, Inbred C57BL
- Disease Models, Animal
- Mammals