Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants.
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.
Greene
Jessica C
JC
Department of Genome Sciences, University of Washington, P.O. Box 357730, Seattle, WA 98195, USA.
Whitworth
Alexander J
AJ
Kuo
Isabella
I
Andrews
Laurie A
LA
Feany
Mel B
MB
Pallanck
Leo J
LJ
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D003001:Cloning, Molecular; D004330:Drosophila / Q000235:genetics* / Q000254:growth & development; D008025:Ligases / Q000235:genetics*; D008136:Longevity; D008297:Male; D008928:Mitochondria / Q000235:genetics* / Q000473:pathology*; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology*; D016296:Mutagenesis; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics; D011994:Recombinant Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013087:Spermatids / Q000473:pathology; D044767:Ubiquitin-Protein Ligases
D011994:Recombinant Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases