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J Neurosci. 2014 Oct 22;34(43):14304-17. doi: 10.1523/JNEUROSCI.0930-14.2014.

Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons.

Author information

1
Gladstone Institute of Neurological Disease, San Francisco, California 94158.
2
Department of Neurology and.
3
Department of Pathology, University of California, San Francisco, San Francisco, California 94158.
4
Department of Neurosciences, Translational Neurosciences Institute, University of California, San Diego, La Jolla, California 92093.
5
Department of Neurology and Graduate Programs in Neuroscience and Biomedical Sciences, University of California, San Francisco, San Francisco, California 94158.
6
Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, and.
7
Graduate Programs in Neuroscience and Biomedical Sciences, University of California, San Francisco, San Francisco, California 94158, Department of Pathology, University of California, San Francisco, San Francisco, California 94158.
8
Gladstone Institute of Neurological Disease, San Francisco, California 94158, Department of Neurology and Graduate Programs in Neuroscience and Biomedical Sciences, University of California, San Francisco, San Francisco, California 94158, ken.nakamura@gladstone.ucsf.edu.

Abstract

Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson's disease (PD). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. To study one aspect of mitochondrial dynamics-mitochondrial fission-in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). Drp1 loss rapidly eliminates the DA terminals in the caudate-putamen and causes cell bodies in the midbrain to degenerate and lose α-synuclein. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents (Ih) is spared, despite near complete loss of their axonal mitochondria. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons.

KEYWORDS:

Drp1; Parkinson's disease; axon; mitochondria; neurodegeneration

PMID:
25339743
PMCID:
PMC4205554
DOI:
10.1523/JNEUROSCI.0930-14.2014
[Indexed for MEDLINE]
Free PMC Article

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