title: Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons.
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.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors.forename: Amandine
authors.initials: A
authors.lastname: Berthet
authors.affiliation: Department of Neurology and.
authors.forename: Elyssa B
authors.initials: EB
authors.lastname: Margolis
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors.forename: Jue
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California 94158.
authors.forename: Ivy
authors.initials: I
authors.lastname: Hsieh
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, California 94158.
authors.forename: Jiasheng
authors.identifier: http://orcid.org/0000-0001-6097-1384
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Neurosciences, Translational Neurosciences Institute, University of California, San Diego, La Jolla, California 92093.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Hnasko
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, California 94158.
authors.forename: Jawad
authors.initials: J
authors.lastname: Ahmad
authors.affiliation: Department of Neurology and Graduate Programs in Neuroscience and Biomedical Sciences, University of California, San Francisco, San Francisco, California 94158.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Edwards
authors.affiliation: Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21287, and.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: 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.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Ken
authors.initials: K
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D034281:Dynamins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D008636:Mesencephalon / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D063154:Mitochondrial Dynamics / Q000502:physiology*; D009924:Organ Culture Techniques
chemical_list: C486391:Dnm1l protein, mouse; D034281:Dynamins
keywords: Drp1; Parkinson's disease; axon; mitochondria; neurodegeneration