Annie Huang

 Background:  Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and α-synuclein protein aggregation.¹ Existing treatments only alleviate symptoms and do not stop disease progression.¹ About 90-95% of PD cases are sporadic, while 5-10% are familial forms of the disease.¹ Advances in identifying monogenic causes of early-onset familial PD, such as variants in genes encoding α-synuclein, tau, and glucocerebrosidase, have been made in recent years.¹ Abnormal protein aggregation and malfunctioning degradation pathways, such as autophagy and lysosome dysfunctions, are known to be the cause of PD.¹ Some of these conditions are caused by primary genetic mutations directly or indirectly affecting components of the autophagy machinery.² In addition to the genetic mutations of PD, AMPK, mTOR, and TFEB are important regulators of autophagy, and activation of the AMPK-mTOR-TFEB axis could promote α -synuclein clearance, providing a promising strategy for treating PD.² Exploring potential treatment options for PD requires understanding the linkage between PD and AMPK/mTOR, given that current therapies only target non-motor and motor symptoms without the ability to delay or stop disease progression.²

Objective: Our objective was to understand the mechanisms between PD and the AMPK/mTOR pathway and its effects on α-synuclein turnover.

 Search Methods: We accessed the publicly available PubMed database from 2017 to 2022 using following keywords: “AMPK/mTOR pathway”, “autophagy”, “Parkinson’s disease”, “α-synuclein turnover”.

 Results: Various studies have investigated the role of autophagy in Parkinson’s disease (PD) and how different molecules can modulate this pathway. Disruption of the autophagy adaptor/receptor protein p62 led to α-synuclein accumulation and Lewy pathology in dopaminergic neurons.³ Overexpression of miR-185 was observed to hinder apoptosis and prevent α-synuclein accumulation in SH-SY5Y cells subjected to MPTP and an AMPK inhibitor. ⁴ Additionally, miR-124 protected dopaminergic neurons by modulating apoptosis and autophagy via the AMPK/mTOR cascade in PD.^4,5 Administration of citronellol promoted autophagic degradation of misfolded proteins, while harmol activated the AMPK-mTOR-TFEB pathway, promoting α-synuclein degradation and improving motor impairment in PD. ^6,7 Harmol induced the nuclear translocation of TFEB and increased the expression of lysosomal and autophagy markers, suggesting that it promotes autophagy flux and lysosomal biogenesis.⁶

Conclusion: The studies suggest that disruption of the autophagy pathway can lead to α-synuclein accumulation and Lewy pathology in dopaminergic neurons in Parkinson’s disease (PD), while overexpression of certain microRNAs can hinder apoptosis and prevent α-synuclein accumulation.^1,2,3 Furthermore, administration of citronellol and harmol has been observed to promote autophagic degradation of misfolded proteins and activate the AMPK-mTOR-TFEB pathway, respectively, leading to α-synuclein degradation and improved motor impairment in PD. ^6,7 Harmol also promoted autophagy flux and lysosomal biogenesis.⁶ However, further research is needed to fully understand its mechanisms of action in different animal models.⁶

Works Cited:

1. Hou X, Watzlawik JO, Fiesel FC, Springer W. Autophagy in Parkinson’s Disease. J Mol Biol. 2020;432(8):2651-2672. doi:10.1016/j.jmb.2020.01.037
2. Deneubourg C, Ramm M, Smith LJ, et al. The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy. 2022;18(3):496-517. doi:10.1080/15548627.2021.1943177
3. Sato S, Uchihara T, Fukuda T, et al. Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice. Sci Rep. 2018;8(1):2813. Published 2018 Feb 12. doi:10.1038/s41598-018-21325-w
4. Wen Z, Zhang J, Tang P, Tu N, Wang K, Wu G. Overexpression of miR-185 inhibits autophagy and apoptosis of dopaminergic neurons by regulating the AMPK/mTOR signaling pathway in Parkinson’s disease. Mol Med Rep. 2018;17(1):131-137. doi:10.3892/mmr.2017.7897
5. Wang W, Lv R, Zhang J, Liu Y. circSAMD4A participates in the apoptosis and autophagy of dopaminergic neurons via the miR-29c-3p-mediated AMPK/mTOR pathway in Parkinson’s disease. Mol Med Rep. 2021;24(1):540. doi:10.3892/mmr.2021.12179
6. Xu J, Ao YL, Huang C, et al. Harmol promotes α-synuclein degradation and improves motor impairment in Parkinson’s models via regulating autophagy-lysosome pathway. NPJ Parkinsons Dis. 2022;8(1):100. Published 2022 Aug 6. doi:10.1038/s41531-022-00361-4
7. Jayaraj RL, Azimullah S, Parekh KA, Ojha SK, Beiram R. Effect of citronellol on oxidative stress, neuroinflammation and autophagy pathways in an in vivo model of Parkinson’s disease. Heliyon. 2022;8(11):e11434. Published 2022 Nov 3. doi:10.1016/j.heliyon.2022.e11434