Abstract
Neurons affected in Parkinson’s disease (PD) experience mitochondrial dysfunction and bioenergetic deficits that occur early and promote the disease-related α-synucleinopathy. Emerging findings suggest that the autophagy-lysosome pathway, which removes damaged mitochondria (mitophagy), is also compromised in PD and results in the accumulation of dysfunctional mitochondria. Studies using genetic-modulated or toxin-induced animal and cellular models as well as postmortem human tissue indicate that impaired mitophagy might be a critical factor in the pathogenesis of synaptic dysfunction and the aggregation of misfolded proteins, which in turn impairs mitochondrial homeostasis. Interventions that stimulate mitophagy to maintain mitochondrial health might, therefore, be used as an approach to delay the neurodegenerative processes in PD.
Highlights
Parkinson’s disease (PD) is an incurable chronic progressive disease affecting nearly 2% of the “over 50” population with an approximately estimate of more than 6 million cases worldwide [1]
The mTOR inhibitor rapamycin, which stabilizes the association of mTOR complex and inhibits the kinase activity, is the most widely used small molecule drug which is proved effective in enhancing autophagy activity in many disease models [76,77,78,79,80,81]
Methods to activate autophagy are promising novel therapeutic approaches for PD, a complex scenario is emerging in which the alteration of distinct regulatory steps in autophagy may perturb the homeostasis of the cell, contributing to the disease progression as well [98]
Summary
Parkinson’s disease (PD) is an incurable chronic progressive disease affecting nearly 2% of the “over 50” population with an approximately estimate of more than 6 million cases worldwide [1]. Epidemiological studies have revealed that fewer than 10% of PD cases are inherited from family, whereas the majority of cases are sporadic [3]. Discoveries of genes linked to rare familial forms of PD have confirmed the critical role of genes in the development of PD and made great contributions in understanding the molecular pathogenesis behind this common but complex illness. We consider the roles of autophagy in neuronal health and the pathological mechanisms leading to disease progression to help us seek for potential targets for neuroprotective interventions, which may revolutionize the treatment of this incurable disease
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