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 Ken Nakamura, MD PhD
Assistant Investigator
Gladstone Institute of Neurological Disease
Assistant Professor of Neurology
University of California, San Francisco
Email: ken.nakamura@gladstone.ucsf.edu
Telephone: 415-734-2550
Fax: 415-355-0824
Please direct clinical questions to:
UCSF Movement Disorders Clinic
Telephone: 415-353-2273
Areas of investigation
The research in our laboratory has two broad objectives. The first is to gain insight into the normal physiology of mitochondria in the brain, with a particular emphasis on understanding the biologic functions of mitochondrial dynamics and turnover, and the role of mitochondria in synaptic transmission. The second is to understand how disruption of these mitochondrial functions contributes to the pathogenesis of neurodegenerative diseases, especially Parkinson's disease and Alzheimer's disease. |
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Significance
Mitochondria are dynamic organelles that undergo constant fusion and fission, play important roles in multiple cellular functions including energy production, and are ultimately degraded. However, many aspects of mitochondrial behavior and function are not understood, especially in the brain and at the synapse. Changes in mitochondria also play central and sometimes initiating roles in neurodegeneration, although the underlying mechanisms, or even the nature of the changes themselves, are poorly characterized. Advancing our understanding of the normal behavior and functions of mitochondria is thus a critical step in unraveling how mitochondrial biology is disrupted in disease, and in ultimately designing new mitochondria-based therapies. |
Approaches
We use an array of sophisticated microscopy approaches to study mitochondrial biology in the brain. Mitochondria are visualized live using targeted fluorescent probes, and mitochondrial movement, functions and turnover are imaged in mammalian cells including primary neurons. Transgenic mouse models and genetically modified viral vectors are also used to study mitochondria in vivo, and to determine how human mutations causing Parkinson's disease and Alzheimer's disease disrupt mitochondrial function and produce degeneration. To establish mechanism, we also use in vitro model systems with recombinant proteins and purified mitochondria or artificial membranes.
Contributions
The protein α-synuclein plays a central role in the pathogenesis of Parkinson's disease. Increased expression of synuclein produces rare familial forms, and the protein also accumulates at high levels in sporadic Parkinson's disease, which is far more common. However, the mechanism by which increased synuclein causes Parkinson's disease is not known. Using optical FRET reporters for synuclein conformation, we found that synuclein preferentially binds to mitochondria versus other organelles, apparently because of its high affinity for the acidic phospholipid cardiolipin, which is enriched in mitochondria. In subsequent studies, we found that the expression of synuclein produces a dramatic increase in mitochondrial fragmentation in a range of cell types, including dopamine neurons in transgenic models of Parkinson's disease. The effect is specific to mitochondria versus other organelles, and occurs through a novel mechanism that precedes any evidence of mitochondrial dysfunction or cell toxicity. These findings reveal a new function of synuclein in regulating mitochondrial morphology, and establish a potential mechanism by which synuclein may produce degeneration in Parkinson's disease.
Questions Addressed in Ongoing Studies
- What are the normal functions of mitochondrial fusion and fission in neurons?
- How and why are mitochondria turned over?
- How do mitochondria contribute to synaptic transmission?
- How do Parkinson's disease proteins disrupt mitochondrial function and produce neurodegeneration?
- How does mitochondrial dysfunction contribute to the pathogenesis of Alzheimer's disease?
Selected References
Nakamura K, Nemani VM, Azarbal F, Skibinski G, Levy JM, Egami K, Munishkina L, Zhang J, Gardner B, Wakabayashi J, Sesaki H, Cheng Y, Finkbeiner S, Nussbaum RL, Edwards RH. (2011) Direct membrane association drives mitochondrial fission by the Parkinson's disease-associated protein α-synuclein. J Biol Chem. (Epub ahead of print, “Paper of the Week”)
Nemani VM, Lu W, Berge V, Nakamura K, Ono V, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH. (2010) Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65(1), 66-79.
Nakamura K, Nemani VM, Kaehlcke K, Ott M, Edwards RH. (2008) Optical reporters for the conformation of alpha-synuclein reveal a specific interaction with mitochondria. J Neurosci 28(47), 12305-17.
Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH. (2004) Lipid rafts mediate the synaptic localization of α-synuclein. J Neurosci. 24(30), 6715-6723.
Nakamura K, Bindokas VP, Kowlessur D, Elas M, Milstien S, Marks JD, Halpern HJ, Kang UJ. (2001) Tetrahydrobiopterin scavenges superoxide in dopaminergic neurons. J Biol Chem. 276(37), 34402-7.
Nakamura K, Bindokas VP, Marks JD, Wright DA, Frim DM, Miller RJ, Kang UJ. (2000) The selective toxicity of 1-methyl-4-phenylpyridinium to dopaminergic neurons: the role of mitochondrial complex I and reactive oxygen species revisited. Mol Pharmacol. 58(2), 271-278.
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