Neuroprotective effects of osmotin in Parkinson’s disease-associated pathology via the AdipoR1/MAPK/AMPK/mTOR signaling pathways

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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-hαSyn) 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 α-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 α-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 α-synuclein-induced mice.

Conclusions

Therefore, our findings indicated that osmotin significantly rescued MPTP/α-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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12929-023-00961-z.

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Most cited references 56

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alpha-Synuclein is phosphorylated in synucleinopathy lesions.

Hideo Fujiwara, Masato Hasegawa, Naoshi Dohmae … (2002)

The deposition of the abundant presynaptic brain protein alpha-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. However, specific post-translational modifications that underlie the aggregation of alpha-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of alpha-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.

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Pathological roles of MAPK signaling pathways in human diseases.

Eun Kim, Eui-Ju Choi (2010)

The mammalian family of mitogen-activated protein kinases (MAPKs) includes extracellular signal-regulated kinase (ERK), p38, and c-Jun NH(2)-terminal kinase (JNK), with each MAPK signaling pathway consisting of at least three components, a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK. The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors such as oxidative stress and endoplasmic reticulum stress. These signaling pathways regulate a variety of cellular activities including proliferation, differentiation, survival, and death. Deviation from the strict control of MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers. Persistent activation of the JNK or p38 signaling pathways has been suggested to mediate neuronal apoptosis in AD, PD, and ALS, whereas the ERK signaling pathway plays a key role in several steps of tumorigenesis including cancer cell proliferation, migration, and invasion. In this review, we summarize recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS. Copyright 2010 Elsevier B.V. All rights reserved.

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Non-motor symptoms of Parkinson's disease: diagnosis and management.

Tapan K. Chaudhuri, Mark Healy, … (2006)

The clinical diagnosis of Parkinson's disease rests on the identification of the characteristics related to dopamine deficiency that are a consequence of degeneration of the substantia nigra pars compacta. However, non-dopaminergic and non-motor symptoms are sometimes present before diagnosis and almost inevitably emerge with disease progression. Indeed, non-motor symptoms dominate the clinical picture of advanced Parkinson's disease and contribute to severe disability, impaired quality of life, and shortened life expectancy. By contrast with the dopaminergic symptoms of the disease, for which treatment is available, non-motor symptoms are often poorly recognised and inadequately treated. However, attention is now being focused on the recognition and quantitation of non-motor symptoms, which will form the basis of improved treatments. Some non-motor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with available treatments. Other non-motor symptoms can be more refractory and need the introduction of novel non-dopaminergic drugs. Inevitably, the development of treatments that can slow or prevent the progression of Parkinson's disease and its multicentric neurodegeneration provides the best hope of curing non-motor symptoms.

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Author and article information

Contributors

Jun Sung Park: jsp@gnu.ac.kr

Kyonghwan Choe: k.choe@gnu.ac.kr , k.choe@maastrichtuniversity.nl

Hyeon Jin Lee: lhj4912@gnu.ac.kr

Tae Ju Park: t.park.1@research.gla.ac.uk

Myeong Ok Kim: mokim@gnu.ac.kr

Journal

Journal ID (nlm-ta): J Biomed Sci

Journal ID (iso-abbrev): J Biomed Sci

Title: Journal of Biomedical Science

Publisher: BioMed Central (London )

ISSN (Print): 1021-7770

ISSN (Electronic): 1423-0127

Publication date (Electronic): 11 August 2023

Publication date PMC-release: 11 August 2023

Publication date Collection: 2023

Volume: 30

Electronic Location Identifier: 66

Affiliations

[1 ]GRID grid.256681.e, ISNI 0000 0001 0661 1492, Division of Life Sciences and Applied Life Science (BK 21 Four), College of Natural Science, , Gyeongsang National University, ; Jinju, 52828 Republic of Korea

[2 ]GRID grid.5012.6, ISNI 0000 0001 0481 6099, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), , Maastricht University, ; 6229ER Maastricht, the Netherlands

[3 ]GRID grid.8756.c, ISNI 0000 0001 2193 314X, 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

[4 ]Alz-Dementia Korea Co., Jinju, 52828 Republic of Korea

Article

Publisher ID: 961

DOI: 10.1186/s12929-023-00961-z

PMC ID: 10422754

PubMed ID: 37568205

SO-VID: 2613f3a9-4201-49f7-ade4-745b6be514a7

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 2 May 2023

Date accepted : 5 August 2023

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003725, National Research Foundation of Korea;

Award ID: 2020M3E5D9080660

Custom metadata

ScienceOpen disciplines: Molecular medicine

Keywords: parkinson’s disease,osmotin,α-synuclein,dopaminergic neuron,neuroinflammation

Data availability:

ScienceOpen disciplines: Molecular medicine

Keywords: parkinson’s disease, osmotin, α-synuclein, dopaminergic neuron, neuroinflammation

Neuroprotective effects of osmotin in Parkinson’s disease-associated pathology via the AdipoR1/MAPK/AMPK/mTOR signaling pathways

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Abstract

Background

Methods

Results

Conclusions

Supplementary Information

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Neuronal Signaling

Most cited references 56

alpha-Synuclein is phosphorylated in synucleinopathy lesions.

Pathological roles of MAPK signaling pathways in human diseases.

Non-motor symptoms of Parkinson's disease: diagnosis and management.

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