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Cited by 1,203Parkinson's Disease Mechanisms and TreatmentsMitochondrial Function and PathologyNuclear Receptors and Signaling

Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants

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Greene, Jessica C., Whitworth, Alexander J., Kuo, Isabella, Andrews, Laurie A., Feany, Mel B., Pallanck, Leo J.·2003·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0737556100PMC PMC153051
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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.

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  • Reduction of mitophagy caused by ablation of PINK and Parkin induces mitochondrial dysfunction and increased sensitivity to oxidative stress followed by muscle degeneration.

    “Conversely, reduction of mitophagy caused by the ablation of PINK and Parkin induces mitochondrial dysfunction and increased sensitivity to oxidative stress followed by muscle degeneration [225–228].”

    From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [225]

  • Both excessive autophagy and deficient degradation of cytosolic components contribute to muscle atrophy.

    “Both excessive autophagy [140, 186] and the deficient degradation of cytosolic components [225, 226] contribute to muscle atrophy.”

    From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [225]

  • Parkin loss-of-function in Drosophila resulted in decreased lifespan and increased locomotor defects.

    “whereas Parkin loss-of-function in Drosophila resulted in a decreased lifespan and increased locomotor defects [157,158].”

    From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [157]

  • In Drosophila, knocking out either Parkin or Pink1 caused muscle degeneration that was associated with enlarged mitochondria.

    “Although there are conflicting data regarding the specific effects of these proteins on mitochondrial morphology in mammalian cells, extensive studies in Drosophila revealed that knocking out either gene caused muscle degeneration that was associated with enlarged mitochondria (Clark et al., 2006; Greene et al., 2003).”

    From New insights into the role of mitochondria in aging: mitochondrial dynamics and more (2010) · cites this paper as Greene et al., 2003

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Authors
Greene, J. C., Whitworth, A. J., Kuo, I., Andrews, L. A., Feany, M. B., & Pallanck, L. J.
Affiliations
  • Brigham and Women's Hospital (US)
  • Department of Genome Sciences, University of Washington, P.O. Box 357730, Seattle, WA 98195; and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2003-03-17
Volume
100
Issue
7
Pages
4078-4083
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0737556100
PMC
PMC153051
OpenAlex
W2055124287
Cited by
1,203
References
34
Citations by year
2026: 17 · 2025: 29 · 2024: 34 · 2023: 38 · 2022: 49 · 2021: 64 · 2020: 68 · 2019: 50 · 2018: 64 · 2017: 54 · 2016: 69 · 2015: 56 · 2014: 55 · 2013: 64 · 2012: 67
FWCI
27.97
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS041780, 1R01NS41780-01, 1R01NS41536-01, R01NS041536)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Parkin, Parkinson's disease, autosomal recessive juvenile parkinsonism, mitochondrial dysfunction, muscle degeneration, apoptosis, Drosophila model, ubiquitin-protein ligase, spermatid individualization, male sterility, locomotion defects, lifespan, selective cell death
MeSH terms
Amino Acid Sequence, Animals, Cloning, Molecular, Drosophila, Ligases, Longevity, Male, Mitochondria, Molecular Sequence Data, Nerve Degeneration, Parkinson Disease, Recombinant Proteins, Spermatids, Mutagenesis, Sequence Alignment, Apoptosis, Sequence Homology, Amino Acid, Muscle, Skeletal, Ubiquitin-Protein Ligases

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