Autophagy impairment in Parkinson’s disease: approaches to therapy

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Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative disorders characterized by progressive motor impairment due to the death of dopaminergic neurons in the substantia nigra of the brain. PD affects more than 1% of the population over 60 years of age worldwide. Despite significant progress in understanding the pathogenesis of PD, including genetic and biochemical aspects, current therapies are limited to symptomatic treatment. Recent evidence suggests that impaired autophagy leads to the accumulation of abnormal proteins, particularly α-synuclein, aggregated forms of which are neurotoxic to dopaminergic neurons in the substantia nigra. Notably, PD is predominantly sporadic. However, monogenic forms of the disease have also been described. Among the most common PD forms with known etiology are PD associated with mutations in the GBA1 gene and PD associated with mutations in the LRRK2 gene. Leucine-rich repeat kinase 2 (LRRK2), encoded by the LRRK2 gene, and the lysosomal enzyme glucocerebrosidase (GCase), encoded by the GBA1 gene, are involved in the same endolysosomal pathway. The LRRK2 and GCase dysfunction reported in PD, especially in the case of mutations in the genes encoding them, can lead to impairment of the endolysosomal pathway, lysosomal function, and possibly autophagy. This review highlights the molecular mechanisms of autophagy and prospects for targeted therapy of PD based on the induction of autophagy by influencing key players in this process.

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T. S. Usenko

Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre “Kurchatov Institute”; Pavlov First Saint-Petersburg State Medical University

Author for correspondence.
Email: usenko_ts@pnpi.nrcki.ru
Russian Federation, Gatchina; Saint-Petersburg

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2. Fig. 1. Schematic representation of autophagy processes. a — Chaperone-mediated autophagy; b — microautophagy; c — macroautophagy. From here on: the figures were created using the BioRender program (https://www.biorender.com).

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3. Fig. 2. mTOR complexes and regulation of macroautophagy via the mTORC1 pathway. a — Structure of mTORC1 and mTORC2 complexes; b — activation of mTORC1.

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4. Fig. 3. mTOR-independent regulation of autophagy via the cAMP/EPAC/PLC-IP3, Ca2+/calpain, and inositol (Ins) signaling pathways. Activation of receptors via the α-subunit of heterotrimeric G protein (GSA) and adenylate cyclase (AC) leads to an increase in the level of cyclic AMP (cAMP), which activates the EPAC protein. This then leads to the activation of phospholipase C (PLC), which hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP2) to form inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds to its receptors on the endoplasmic reticulum (ER), which causes the release of Ca2+ ions into the cytoplasm. This activates a family of Ca2+-dependent cysteine ​​proteases, the calpains, which cleave and activate GSA. This in turn enhances AC activity, which increases cAMP levels and creates a feedback loop. PIP2 is hydrolyzed by 5'-phosphatase and inositol phosphatase (IPPase) to inositol-1-phosphate, which is further cleaved by inositol monophosphatase (IMPase) to free inositol, which is required for downstream signaling. Increased intracellular inositol or IP3 levels inhibit autophagosome synthesis.

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5. Fig. 4. Scheme of RNA sequencing and analysis of data from primary culture of peripheral blood macrophages from patients with GBA1-PD, asymptomatic carriers of mutations in the GBA1 gene (GBA1 carriers) and neurologically healthy individuals, as well as samples of SN mice with combined induction of parkinsonism with GCase dysfunction (MPTP+CE), mice with induction of parkinsonism (MPTP), mice with GCase dysfunction (CE) and mice with NaCl injection (control).

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6. Fig. 5. Schematic representation of the main potential autophagy targets for Parkinson's disease therapy.

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