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Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit

Pham, Anh H. and Meng, Shuxia and Chu, Quynh N. and Chan, David C. (2012) Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit. Human Molecular Genetics, 21 (22). pp. 4817-4826. ISSN 0964-6906. PMCID PMC3607482. https://resolver.caltech.edu/CaltechAUTHORS:20121205-091831236

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Abstract

Mitochondria continually undergo fusion and fission, and these dynamic processes play a major role in regulating mitochondrial function. Studies of several genes associated with familial Parkinson's disease (PD) have implicated aberrant mitochondrial dynamics in the disease pathology, but the importance of these processes in dopaminergic neurons remains poorly understood. Because the mitofusins Mfn1 and Mfn2 are essential for mitochondrial fusion, we deleted these genes from a subset of dopaminergic neurons in mice. Loss of Mfn2 results in a movement defect characterized by reduced activity and rearing. In open field tests, Mfn2 mutants show severe, age-dependent motor deficits that can be rescued with L-3,4 dihydroxyphenylalanine. These motor deficits are preceded by the loss of dopaminergic terminals in the striatum. However, the loss of dopaminergic neurons in the midbrain occurs weeks after the onset of these motor and striatal deficits, suggesting a retrograde mode of neurodegeneration. In our conditional knockout strategy, we incorporated a mitochondrially targeted fluorescent reporter to facilitate tracking of mitochondria in the affected neurons. Using an organotypic slice culture system, we detected fragmented mitochondria in the soma and proximal processes of these neurons. In addition, we found markedly reduced mitochondrial mass and transport, which may contribute to the neuronal loss. These effects are specific for Mfn2, as the loss of Mfn1 yielded no corresponding defects in the nigrostriatal circuit. Our findings indicate that perturbations of mitochondrial dynamics can cause nigrostriatal defects and may be a risk factor for the neurodegeneration in PD.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1093/hmg/dds311DOIArticle
http://hmg.oxfordjournals.org/content/21/22/4817PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3607482/PubMed CentralArticle
Additional Information:© 2012 The Author. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Received July 20, 2012; Revised and Accepted July 24, 2012. First published online: July 31, 2012. We thank Andrew D. Steele and Paul H. Patterson for use of equipment and software, Sally A. Kim for advice on organotypic slice cultures and Hsiuchen Chen for advice on mouse crosses. We are grateful to the Chan lab for discussion and comments on the manuscript. This work was supported by the National Institutes of Health (GM062967 to D.C.C.), Howard Hughes Medical Institute and the Thomas Hartman Foundation. Funding to pay the Open Access publication charges for this article was provided by the Howard Hughes Medical Institute. Conflict of Interest statement. None declared.
Funders:
Funding AgencyGrant Number
NIHGM062967
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Thomas Hartman FoundationUNSPECIFIED
Issue or Number:22
PubMed Central ID:PMC3607482
Record Number:CaltechAUTHORS:20121205-091831236
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20121205-091831236
Official Citation: Anh H. Pham, Shuxia Meng, Quynh N. Chu, and David C. Chan Loss of Mfn2 results in progressive, retrograde degeneration of dopaminergic neurons in the nigrostriatal circuit Hum. Mol. Genet. (2012) 21(22): 4817-4826 doi:10.1093/hmg/dds311
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:35812
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:05 Dec 2012 17:40
Last Modified:03 Oct 2019 04:31

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