Mitochondrial pathology and apoptotic muscle degeneration in <i>Drosophila parkin</i> mutants

TLDR

Parkinson’s disease is a common neurodegenerative disorder marked by loss of dopaminergic neurons, with mitochondrial dysfunction identified as a major causative factor whose mechanisms remain poorly understood, and loss‑of‑function mutations in the parkin gene underlie the familial form known as autosomal recessive juvenile parkinsonism. The authors created a Drosophila model of AR‑JP to investigate the molecular mechanisms responsible for selective cell death. Parkin null flies exhibit shortened lifespan, locomotor impairment due to apoptotic muscle cell death, male sterility from spermatid individualization failure, and early mitochondrial pathology, indicating that mitochondrial dysfunction drives tissue‑specific degeneration and may underlie selective neuronal loss in AR‑JP.

Abstract

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Several lines of evidence strongly implicate mitochondrial dysfunction as a major causative factor in PD, although the molecular mechanisms responsible for mitochondrial dysfunction are poorly understood. Recently, loss-of-function mutations in the parkin gene, which encodes a ubiquitin-protein ligase, were found to underlie a familial form of PD known as autosomal recessive juvenile parkinsonism (AR-JP). To gain insight into the molecular mechanism responsible for selective cell death in AR-JP, we have created a Drosophila model of this disorder. Drosophila parkin null mutants exhibit reduced lifespan, locomotor defects, and male sterility. The locomotor defects derive from apoptotic cell death of muscle subsets, whereas the male sterile phenotype derives from a spermatid individualization defect at a late stage of spermatogenesis. Mitochondrial pathology is the earliest manifestation of muscle degeneration and a prominent characteristic of individualizing spermatids in parkin mutants. These results indicate that the tissue-specific phenotypes observed in Drosophila parkin mutants result from mitochondrial dysfunction and raise the possibility that similar mitochondrial impairment triggers the selective cell loss observed in AR-JP.