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A 2020 publication in the MDPI journal, Biomolecules looks at targeting a-syn for PD therapeutics. PD is characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy Bodies (cytoplasmic inclusions). The Lewy Bodies are clumps of protein that can build up and create problems in the brain. The Lewy Bodies contain the aggregated a-synuclein protein that can propagate throughout the brain. Many PD studies have looked at ways of inhibiting a-synuclein accumulation to ease PD symptoms. There are various approaches to a-syn inhibition and multiple clinical trials that examine the link between PD and a-syn, with the hope that a treatment may be found for PD using a-syn. Given the central role of α-syn in PD pathology and progression, α-syn met the criteria to be a tantalizing and evident therapeutic target for PD. Promising strategies include predominantly immunization, anti-aggregative molecules, and an increase in α-syn clearance.
This short, enlightening video clip is an extract from a FoundMyFitness interview with Dr. Guido Kroemer. PD is characterized by protein aggregation of a-synuclein and mitochondrial dysfunction, partly due to mitophagy failure. A recently proposed strategy in preventing (or perhaps treating) neurodegenerative diseases like PD is to starve the cells or use biochemical methods to induce general autophagy and thus help the cell rid itself of protein aggregates. Here Dr. Kroemer describes how mitophagy contributes to the pathophysiology of neurodegenerative diseases like PD and Alzheimer’s and how autophagy might mitigate these processes.
A study by Dr. Yue published by the Michal J. Fox Foundation tested the hypothesis that neuronal autophagy is critical for the regulation of alpha-synuclein protein levels and protective against neuronal death; dysfunction of autophagy predisposes to the pathogenesis of PD in dopamine neurons. This was done by establishing conditional knock-out mice in which an essential autophagy gene, Atg7, is deleted specifically in dopamine neurons. These pre-clinical models were used to investigate whether alpha-synuclein wildtype or PD-mutant A53T will be accumulated and deposited into Lewy body-like inclusions in the mutant dopamine neurons. In addition, they studied the effect of inactivation of autophagy on oxidative stress level, striatal dopamine content, and dopamine neuron degeneration. results suggest that neuronal autophagy is critical for the regulation of alpha-synuclein protein levels and protective against neuronal death; dysfunction of autophagy may predispose dopamine neuron to PD-like pathology.
A 2019 study published by NCBI discusses the active participation of autophagy impairment in alpha-synuclein accumulation and propagation, as well as alpha-synuclein-independent neurodegenerative processes in the field of synucleinopathy. There is genetic and post-mortem evidence suggesting that autophagy is involved in synucleinopathies. Also, studies demonstrate the role of autophagy in the pathology of synucleinopathy. α-syn is mainly degraded by both macroautophagy and chaperone-mediated autophagy. Thus, autophagy defects induce intracellular α-syn accumulation, participating in its aggregative state towards the formation of α-syn-positive intracytoplasmic inclusions. Plus, autophagy defects also increase the α-syn secretion by the non-autophagic exosomal pathway, leading to increased cell-to-cell transmission of the protein, and thus the propagation of the α-syn-linked pathology in different brain regions of the CNS. However, autophagy defects also cause detriment effects in cellular homeostasis: (i) lysosomal impairment through structural or functional defects leads to accumulation of non-degraded products and increased production of ROS; (ii) decreased mitophagy leads to neuronal bioenergetic imbalance, and (iii) defective cargo trafficking impairs the addressing of vesicles to lysosomal clearance. There is increasing evidence that inducing the autophagy pathways (by natural, chemical, or genetic approaches), has become a relevant therapeutic approach to counteract the deleterious effects of autophagy impairment in synucleinopathy.