Abstract
Alpha-Synuclein (α-Syn) accumulation is central to the pathogenesis of Parkinson’s disease (PD), hence the quest for finding potential therapeutics that may promote the α-Syn clearance is the need of the hour. To this, activation of the evolutionarily conserved protein and key regulator of the autophagy, 5’AMP-activated protein kinase (AMPK) is well-known to induce autophagy and subsequently the clearance of α-Syn aggregates. Alpha-mangostin (AM) a polyphenolic xanthone obtained from Garcinia Mangostana L. was previously reported to activate AMPK-dependent autophagy in various pre-clinical cancer models. However, no studies evidenced the effect of AM on AMPK-dependent autophagy activation in the PD. Therefore, the present study aimed to investigate the neuroprotective activity of AM in the chronic rotenone mouse model of PD against rotenone-induced α-Syn accumulation and to dissect molecular mechanisms underlying the observed neuroprotection. The findings showed that AM exerts neuroprotection against rotenone-induced α-Syn accumulation in the striatum and cortex by activating AMPK, upregulating autophagy (LC3II/I, Beclin-1), and lysosomal (TFEB) markers. Of note, an in-vitro study utilizing rat pheochromocytoma cells verified that AM conferred the neuroprotection only through AMPK activation, as the presence of inhibitors of AMPK (dorsomorphin) and autophagy (3-methyl adenine) failed to mitigate rotenone-induced α-Syn accumulation. Moreover, AM also counteracted rotenone-induced behavioral deficits, oxidative stress, and degeneration of nigro-striatal dopaminergic neurons. In conclusion, AM provided neuroprotection by ameliorating the rotenone-induced α-Syn accumulation through AMPK-dependent autophagy activation and it can be considered as a therapeutic agent which might be having a higher translational value in the treatment of PD.
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Data availability
The data that supports the findings of this study are available from the corresponding authors upon reasonable request.
Abbreviations
- AM:
-
Alpha-mangostin
- AMPK:
-
5’AMP-activated protein kinase
- ANOVA:
-
Analysis of variance
- APS:
-
Ammonium persulfate
- α-Syn:
-
Alpha-Synuclein
- Atg:
-
Autophagy-related gene
- BCA:
-
Bicinchoninic acid
- CMC:
-
Carboxymethylcellulose
- CPCSEA:
-
Committee for the Purpose of Control and Supervision of Experiments on Animals
- DAergic:
-
Dopaminergic
- DTNB:
-
5,5-dithiobis (2-nitrobenzoic acid)
- GSH:
-
Reduced glutathione
- H2O2 :
-
Hydrogen peroxide
- HRP:
-
Horseradish peroxidase
- IAEC:
-
Institutional Animal Ethics Committee
- LBs:
-
Lewy bodies
- LC3B:
-
Light chain-3B
- 3-MA:
-
3-methyl adenine
- MDA:
-
Malondialdehyde
- MPP+ :
-
1-methyl-4-phenylpyridinium
- OD:
-
Optical density
- PBS:
-
Phosphate buffer saline
- PC12:
-
Pheochromocytoma
- PD:
-
Parkinson’s disease
- PEG:
-
Polyethylene glycol
- PFA:
-
Paraformaldehyde
- PMSF:
-
Phenylmethyl sulfonyl fluoride
- PVDF:
-
Polyvinylidene difluoride
- RBW:
-
Round beam walk
- RIPA:
-
Radioimmunoprecipitation assay
- ROS:
-
Reactive oxygen species
- SDS:
-
Sodium dodecyl sulfate
- SH-SY5Y:
-
Neuroblastoma
- SLS:
-
Sodium lauryl sulfate
- SNc:
-
Substantia nigra pars compacta
- TBA:
-
Thiobarbituric acid
- TBARS:
-
TBA-reactive substance assay
- TEMED:
-
Tetramethyl-ethylenediamine
- TFEB:
-
Transcription factor-EB
- TH:
-
Tyrosine hydroxylase
- Ulk-1:
-
Unc-51 like autophagy activating kinase
- VTA:
-
Ventral tegmental area
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Funding
This work was supported by the seed fund of the National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad. Dr. Amit Khairnar gratefully acknowledges the support of the Ramalingaswami Fellowship from the Department of Biotechnology, India.
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Both P.P. and N.S. contributed equally to this work. We declare that all authors made fundamental contributions to the manuscript. P.P. and A.M.K. designed the study. P.P., N.S., A.G., M.S., and A.A.S. conducted experiments. P.P., N.S., and A.G. analyzed the data. P.P., N.S., M.S., S.C., and A.M.K. participated in the interpretation and writing of the manuscript. A.K. and A.M.K. advised the experiments. All authors read and approved the final manuscript.
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Parekh, P., Sharma, N., Sharma, M. et al. AMPK-dependent autophagy activation and alpha-Synuclein clearance: a putative mechanism behind alpha-mangostin’s neuroprotection in a rotenone-induced mouse model of Parkinson’s disease. Metab Brain Dis 37, 2853–2870 (2022). https://doi.org/10.1007/s11011-022-01087-1
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DOI: https://doi.org/10.1007/s11011-022-01087-1