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Research Article

Analysis of neural subtypes reveals selective mitochondrial dysfunction in dopaminergic neurons from parkin mutants

Jonathon L. Burman, Selina Yu, Angela C. Poole, Richard B. Decal, and Leo Pallanck
  1. aDepartment of Genome Sciences, University of Washington, Seattle, WA 98195;
  2. bInstitute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan; and
  3. cDepartment of Microbiology, Cornell University, Ithaca, NY 14853

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PNAS June 26, 2012 109 (26) 10438-10443; https://doi.org/10.1073/pnas.1120688109
Jonathon L. Burman
aDepartment of Genome Sciences, University of Washington, Seattle, WA 98195;
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Selina Yu
aDepartment of Genome Sciences, University of Washington, Seattle, WA 98195;
bInstitute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan; and
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Angela C. Poole
aDepartment of Genome Sciences, University of Washington, Seattle, WA 98195;
cDepartment of Microbiology, Cornell University, Ithaca, NY 14853
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Richard B. Decal
aDepartment of Genome Sciences, University of Washington, Seattle, WA 98195;
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Leo Pallanck
aDepartment of Genome Sciences, University of Washington, Seattle, WA 98195;
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  • For correspondence: pallanck@u.washington.edu
  1. Edited by Barry Ganetzky, University of Wisconsin, Madison, WI, and approved May 9, 2012 (received for review December 15, 2011)

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Abstract

Studies of the familial Parkinson disease-related proteins PINK1 and Parkin have demonstrated that these factors promote the fragmentation and turnover of mitochondria following treatment of cultured cells with mitochondrial depolarizing agents. Whether PINK1 or Parkin influence mitochondrial quality control under normal physiological conditions in dopaminergic neurons, a principal cell type that degenerates in Parkinson disease, remains unclear. To address this matter, we developed a method to purify and characterize neural subtypes of interest from the adult Drosophila brain. Using this method, we find that dopaminergic neurons from Drosophila parkin mutants accumulate enlarged, depolarized mitochondria, and that genetic perturbations that promote mitochondrial fragmentation and turnover rescue the mitochondrial depolarization and neurodegenerative phenotypes of parkin mutants. In contrast, cholinergic neurons from parkin mutants accumulate enlarged depolarized mitochondria to a lesser extent than dopaminergic neurons, suggesting that a higher rate of mitochondrial damage, or a deficiency in alternative mechanisms to repair or eliminate damaged mitochondria explains the selective vulnerability of dopaminergic neurons in Parkinson disease. Our study validates key tenets of the model that PINK1 and Parkin promote the fragmentation and turnover of depolarized mitochondria in dopaminergic neurons. Moreover, our neural purification method provides a foundation to further explore the pathogenesis of Parkinson disease, and to address other neurobiological questions requiring the analysis of defined neural cell types.

  • autophagy
  • fission
  • FACS
  • glia
  • flow cytometry

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: pallanck{at}u.washington.edu.
  • Author contributions: J.L.B., A.C.P., and L.P. designed research; J.L.B., S.Y., A.C.P., and R.B.D. performed research; J.L.B., A.C.P., and L.P. contributed new reagents/analytic tools; J.L.B. and L.P. analyzed data; and J.L.B. and L.P. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1120688109/-/DCSupplemental.

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Mitochondrial dysfunction in dopaminergic neurons
Jonathon L. Burman, Selina Yu, Angela C. Poole, Richard B. Decal, Leo Pallanck
Proceedings of the National Academy of Sciences Jun 2012, 109 (26) 10438-10443; DOI: 10.1073/pnas.1120688109

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Mitochondrial dysfunction in dopaminergic neurons
Jonathon L. Burman, Selina Yu, Angela C. Poole, Richard B. Decal, Leo Pallanck
Proceedings of the National Academy of Sciences Jun 2012, 109 (26) 10438-10443; DOI: 10.1073/pnas.1120688109
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