PMID- 37568205 OWN - NLM STAT- MEDLINE DCOM- 20230816 LR - 20231118 IS - 1423-0127 (Electronic) IS - 1021-7770 (Print) IS - 1021-7770 (Linking) VI - 30 IP - 1 DP - 2023 Aug 11 TI - Neuroprotective effects of osmotin in Parkinson's disease-associated pathology via the AdipoR1/MAPK/AMPK/mTOR signaling pathways. PG - 66 LID - 10.1186/s12929-023-00961-z [doi] LID - 66 AB - 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-halphaSyn) 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 alpha-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 alpha-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 alpha-synuclein-induced mice. CONCLUSIONS: Therefore, our findings indicated that osmotin significantly rescued MPTP/alpha-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. CI - (c) 2023. National Science Council of the Republic of China (Taiwan). FAU - Park, Jun Sung AU - Park JS AD - Division of Life Sciences and Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. FAU - Choe, Kyonghwan AU - Choe K AD - Division of Life Sciences and Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. AD - Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, 6229ER, Maastricht, the Netherlands. FAU - Lee, Hyeon Jin AU - Lee HJ AD - Division of Life Sciences and Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. FAU - Park, Tae Ju AU - Park TJ AD - Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences (MVLS), University of Glasgow, Glasgow, G12 0ZD, UK. FAU - Kim, Myeong Ok AU - Kim MO AD - Division of Life Sciences and Applied Life Science (BK 21 Four), College of Natural Science, Gyeongsang National University, Jinju, 52828, Republic of Korea. mokim@gnu.ac.kr. AD - Alz-Dementia Korea Co., Jinju, 52828, Republic of Korea. mokim@gnu.ac.kr. LA - eng GR - 2020M3E5D9080660/National Research Foundation of Korea/ PT - Journal Article DEP - 20230811 PL - England TA - J Biomed Sci JT - Journal of biomedical science JID - 9421567 RN - 0 (alpha-Synuclein) RN - 0 (Neuroprotective Agents) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Humans MH - Mice MH - Animals MH - *Parkinson Disease/metabolism MH - alpha-Synuclein/genetics/metabolism/pharmacology MH - *Neuroprotective Agents/pharmacology MH - AMP-Activated Protein Kinases/metabolism MH - Substantia Nigra/metabolism MH - Signal Transduction MH - Dopaminergic Neurons/metabolism MH - TOR Serine-Threonine Kinases/genetics/metabolism/pharmacology MH - Mice, Inbred C57BL MH - Disease Models, Animal MH - Mammals PMC - PMC10422754 OTO - NOTNLM OT - Dopaminergic neuron OT - Neuroinflammation OT - Osmotin OT - Parkinson's disease OT - alpha-Synuclein COIS- The authors declare that they have no competing interests. EDAT- 2023/08/12 10:41 MHDA- 2023/08/16 06:42 PMCR- 2023/08/11 CRDT- 2023/08/11 23:38 PHST- 2023/05/02 00:00 [received] PHST- 2023/08/05 00:00 [accepted] PHST- 2023/08/16 06:42 [medline] PHST- 2023/08/12 10:41 [pubmed] PHST- 2023/08/11 23:38 [entrez] PHST- 2023/08/11 00:00 [pmc-release] AID - 10.1186/s12929-023-00961-z [pii] AID - 961 [pii] AID - 10.1186/s12929-023-00961-z [doi] PST - epublish SO - J Biomed Sci. 2023 Aug 11;30(1):66. doi: 10.1186/s12929-023-00961-z.