A Cleaning Crew: The Pursuit of Autophagy in Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is the second-most common neurodegenerative disorder, neuropathologically characterized by the aggregation of misfolded α-synuclein (α-syn) protein, which appears to be central to the onset and progression of PD pathology. Evidence from pioneering studies has highly advocated the existence of impaired autophagy pathways in the brains of PD patients. Autophagy is an evolutionarily conserved, homeostatic mechanism for minimizing abnormal protein aggregates and facilitating organelle turnover. Any aberration in constitutive autophagy activity results in the aggregation of misfolded α-syn, which, in turn, may further inhibit their own degradationleading to a vicious cycle of neuronal death. Despite the plethora of available literature, there are still lacunas existing in our understanding of the exact cellular interplay between autophagy impairment and α-syn accumulation-mediated neurotoxicity. In this context, clearance of aggregated α-syn via up-regulation of the autophagy–lysosomal pathway could provide a pharmacologically viable approach to the treatment of PD. The present Review highlights the basics of autophagy and detrimental cross-talk between α-syn and chaperone-mediated autophagy, and α-syn and macroautophagy. It also depicts the interaction between α-syn and novel targets, LRRK2 and mTOR, followed by the role of autophagy in PD from a therapeutic perspective. More importantly, it further updates the reader’s understanding of various newer therapeutic avenues that may accomplish disease modification via promoting clearance of toxic α-syn through activation of autophagy.

Co-Transmission of Alpha-Synuclein and TPPP/p25 Inhibits Their Proteolytic Degradation in Human Cell Models

“…Indeed, genetic studies have revealed extensive links between autophagy and neurodegenerative diseases, and disruptions to autophagy may contribute to the development of these diseases. Since both reduced and excessive autophagy can be detrimental, the modulation of autophagy has been proposed as a new, effective way for treating some types of neurodegenerative diseases ( Mputhia et al, 2019 ; Parekh et al, 2019 ; Djajadikerta et al, 2020 ). Rapamycin, an allosteric mTOR inhibitor, is one of the most frequently studied autophagy inducers ( Bove et al, 2011 ); it acts by increasing lysosomal biogenesis by avoiding autophagosome accumulation and neuronal toxicity ( Dehay et al, 2010 ).…”

Apelin-13 Protects Dopaminergic Neurons against Rotenone—Induced Neurotoxicity through the AMPK/mTOR/ULK-1 Mediated Autophagy Activation

“…More importantly, apelin-13 induced autophagy in rotenone treated cells, as indicated by the higher ratio of LC3B-II/LC3B-I, less p62, and α-synuclein accumulated in the cells. Autophagy dysfunction was supposed in α-synuclein aggregation, therefore, clearance of aggregated α-synuclein, via up-regulation of the autophagy-lysosomal pathway, could provide a pharmacologically viable approach to the treatment of PD [58,59]. Considering the presence of autophagy impairment in rotenone models, these results indicate that apelin-13 might serve as an autophagy inducer and exert protective effects against rotenone-induced neurotoxicity.…”

A Potential Innovative Therapy for Parkinson’s Disease: Selective Destruction of the Pathological Assemblies of Alpha-Synuclein

“…SYN interaction with mitochondria occurs at higher protein expression or impaired chaperone-SYN ratio; therefore, the pathological conditions result in the failing of its CMA-derived proteolytic degradations [24]. Therapeutic strategies aiming to increase the SYN degradation through activation of these clearance pathways have thus been deeply explored in order to re-establish physiological levels of the protein and prevent its accumulation in PD [25,42,43]. The most interactions of SYN with mitochondria occur in cells in the case of oxidative stress [44] that can promote SYN aggregation associated with mitochondrial dysfunction [45,46].…”