Targeting mitophagy in neurodegenerative diseases

Abstract

Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement — namely, USP30 inhibitors and PINK1 activators — are entering phase I clinical trials for the first time. Impaired mitophagy leading to the accumulation of damaged mitochondria is associated with the onset and progression of neurodegenerative diseases. This Review provides an overview of the molecular pathways of mitophagy regulation in neurons, discusses evidence implicating mitophagy impairment in the pathogenesis of neurodegenerative diseases and assesses small-molecule-based therapeutic approaches aimed at selective mitophagy enhancement.