Autophagy and Redox Homeostasis in Parkinson's: A Crucial Balancing Act

Abstract

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated primarily from endogenous biochemical reactions in mitochondria, endoplasmic reticulum (ER), and peroxisomes. Typically, ROS/RNS correlate with oxidative damage and cell death; however, free radicals are also crucial for normal cellular functions, including supporting neuronal homeostasis. ROS/RNS levels influence and are influenced by antioxidant systems, including the catabolic autophagy pathways. Autophagy is an intracellular lysosomal degradation process by which invasive, damaged, or redundant cytoplasmic components, including microorganisms and defunct organelles, are removed to maintain cellular homeostasis. This process is particularly important in neurons that are required to cope with prolonged and sustained operational stress. Consequently, autophagy is a primary line of protection against neurodegenerative diseases. Parkinson's is caused by the loss of midbrain dopaminergic neurons (mDANs), resulting in progressive disruption of the nigrostriatal pathway, leading to motor, behavioural, and cognitive impairments. Mitochondrial dysfunction, with associated increases in oxidative stress, and declining proteostasis control, are key contributors during mDAN demise in Parkinson's. In this review, we analyse the crosstalk between autophagy and redoxtasis, including the molecular mechanisms involved and the detrimental effect of an imbalance in the pathogenesis of Parkinson's.

Figure 1

Redox regulation of autophagy. Free radicals in the cell are mainly generated in mitochondria, peroxisomes, and ER; thus, a tightly regulated process to ensure proper functionality and turnover is crucial for cell survival (i.e., degradation by selective autophagy, e.g., mitophagy (i) or pexophagy (ii)). Under certain conditions (e.g., oxidative damage), autophagy is induced as an antioxidant pathway, and this leads to the initiation and nucleation of autophagy assembly sites (e.g., at the ER), with subsequent formation of the autophagosome, and eventual fusion with a lysosome to form a degradative autolysosome. ROS/RNS have the potential to regulate autophagy via upstream regulators, including proteins involved in the UPR system and the autophagy inhibitor mTOR, as well as redox modification in the cytoskeleton, affecting autophagosome transport. In addition, direct modifications in proteins involved in the autophagy process have also been identified including those involved in ATG8 cleavage and conjugation (i.e., ATG4 involved in LC3 cleavage; ATG3 and ATG7 involved in ATG8 lipidation), PI3KC3 activation and cargo recognition (e.g., p62/SQSTM1), and in selective autophagy (e.g., ATM in pexophagy and PINK1, Parkin and DJ-1 for mitophagy) (see the text for full description). Finally, autophagy and redoxtasis crosstalk is evident at the transcriptional level, with several transcription factors involved in autophagy regulation subject to redox modification. Some transcription factors regulate both redox levels and the autophagy process (e.g., NRF2, FOXOs, and p53). P (green): highlights phosphorylation events; Ub (black): highlights ubiquitination events; Ox (red): highlights sites for redox regulation of autophagy.

Figure 2

Oxidative stress and autophagy dysregulation in Parkinson's. Oxidative stress and autophagy dysregulation are interconnected in the dopaminergic neurons affected in Parkinson's. In addition, several conditions contribute to this destructive imbalance leading to neuronal death and progressive neurodegeneration, including a reduction in antioxidant pathways (e.g., a reduction in endogenous antioxidant mechanisms and antioxidant transcription factors); ER stress; mitochondrial dysfunction; mutations in key proteins modulating these processes (familial Parkinson's); disruption of the cytoskeleton; UPS dysfunction; neuroinflammation; high levels of calcium and iron, leading to neurotoxicity; neurotoxins (e.g., MPTP and rotenone); and α-syn aggregation in Lewy's bodies.