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Neuroscience Graduate Program at UCSF

Faculty - Ken Nakamura, M.D./Ph.D

Mitochondrial Biology in Neurodegenerative Disease


Research Description

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 (PD) and Alzheimer’s disease (AD).

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 PD and AD 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 alpha-synuclein plays a central role in the pathogenesis of PD.  Increased expression of synuclein produces rare familial forms, and the protein also accumulates at high levels in sporadic PD, which is far more common.  However, the mechanism by which increased synuclein causes PD 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 PD.  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 PD.

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Current Projects

Roles of mitochondrial fusion and fission in neurons

Mechanisms of mitochondrial turnover in neurons

Functions of mitochondria in synaptic transmission

Mitochondrial dysfunction in the pathogenesis of Parkinson’s disease

Mitochondrial dysfunction in the pathogenesis of Alzheimer’s disease

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Lab Members

Amandine Berthet, PhD, Postdoctoral Fellow

Dominik Haddad, PhD, Postdoctoral Fellow

Bryce Mendelsohn, MD, PhD, Postdoctoral Fellow

Divya Pathak, PhD, Postdoctoral Fellow

Wei Lin, Research Associate

Lauren Shields, Graduate Student

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Selected Publications

Skibinski G, Nakamura K, Cookson M, Finkbeiner S. (2014) Mutant LRRK2 Toxicity in Neurons Depends on LRRK2 Levels and Synuclein But Not Kinase Activity or Inclusion Bodies. J Neuroscience. 34(2), 418-33

Ho, L, Titus AS, Bannerjee KK, George S, Lin W, Saha AK, Nakamura K, Gut P, Verdin E, Kolthur U. (2013) SIRT4 Regulates ATP homeostasis and mediates a retrograde signaling via AMPK. Aging. 5(11), 835-849

Pathak D, Berthet A, Nakamura K. (2013) Energy failure- does it contribute to neurodegeneration? (Ann Neurol. 74(4), 506-516

Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, Schneider DS, Nakamura K, Shiloh MU, Cox JS. (2013) The ubiquitin ligase PARKIN is required for autophagy and host resistance to intracellular pathogens. Nature. 501 (7468):512-6 

Hertz NT, Berthet A, Sos ML, Thorn KS, Burlingame AL, Nakamura K, Shokat KM. (2013) A neo-substrate that amplifies catalytic activity of Parkinson's disease related kinase PINK1. Cell. 154 (737-747).

Yoshida S, Tsutsumi S, Muhlebach G, Sourbier C, Lee MJ, Lee S, Vartholomaiou E, Tatakoro M, Beebe K, Miyajima N, Mohney RP, Chen Y, Hasumi H, Xu W, Fukushima H, Nakamura K, Koga F, Kihara K, Trepel J, Picard D, Neckers L. (2013) Molecular chaperone TRAP1 regulates a metabolicswitch between mitochondrial respiration and aerobic glycolysis.  Proc Natl Acad Sci USA. 110(17), E1604-12

Nakamura, K. (2013) α-Synuclein and mitochondria: partners in crime? Neurotherapeutics. 10(3), 391-9.

Itoh K, Nakamura K, Iijima M, Sesaki H. (2012) Mitochondiral Dynamics in Neurodegeneration. Trends Cell Biol. 23(2), 64-71

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, Masliah E, Edwards RH. Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. J Biol Chem. 2011 Jun 10; 286(23):20710-26. (selected by JBC editors as one of the 20 “Best of 2011", top paper from Neurobiology in 2011)

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.

Fortin DL, Nemani VM, Nakamura K, Edwards RH. (2010) The behavior of alpha-synuclein in neurons. Mov Disord. 25 Suppl 1: S21-6.

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.

Nakamura K, Edwards RH. (2007) Physiology versus pathology in Parkinson’s disease.  Proc Natl Acad Sci USA. 104(29), 11867-8.

Nakamura K, Christine CW, Starr PA, Marks WJ. (2007) Effects of unilateral subthalamic and pallidal deep brain stimulation on fine motor functions in Parkinson’s disease.  Mov Disord. 22(5), 619-26.

Nakamura K, Aminoff MJ. (2007) Huntington’s disease: clinical characteristics, pathogenesis and therapies.  Drugs Today. 43(2), 97-116.

Nakamura K, Kang UJ. (2006) Trophic factor delivery by gene therapy. In: Textbook of neural repair and rehabilitation (eds Selzer ME, Cohen L, Gage FH, Clarke S and Duncan PW), Cambridge University Press, Cambridge, UK, Chapter 29, pp 532-547.

Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH. (2004) Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci. 24(30), 6715-6723.

Kang UJ, Nakamura K. (2003) Potential of gene therapy for pediatric neurotransmitter diseases: lessons from Parkinson's disease.  Ann Neurol. 54 Suppl 6, S103-9.

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, Ahmed M, Barr E, Leiden J, Kang UJ. (2000)  The localization and functional contribution of striatal aromatic L-amino acid decarboxylase to L-3,4-dihydroxyphenylalanine decarboxylation  in rodent parkinsonian models.  Cell Transplantation. 9(5), 567-576.

Nakamura K, Won L, Heller A, Kang UJ. (2000) Preferential resistance of dopaminergic neurons to glutathione depletion in a reconstituted nigrostriatal system.  Brain Res. 873(2), 203-211.

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.

Nakamura K, Wright DA, Wiatr T, Kowlessur D, Milstien S, Lei XG, Kang UJ. (2000) Preferential resistance of dopaminergic neurons to glutathione depletion is independent of cellular glutathione peroxidase and is mediated by tetrahydrobiopterin. J Neurochem. 74(6), 2305-2314.

Nakamura K, Wang W, and Kang UJ. (1997) The role of glutathione in dopaminergic neuronal survival.  J Neurochem. 69, 1850-1858.

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Ken Nakamura, M.D./Ph.D.



Email

ken.nakamura@gladstone.ucsf.edu

Phone

415-734-2550

Office Address

UCSF MC 1230
Gladstone Institute of Neurological  Disease
1650 Owens Street, room 308
San Francisco, CA 94158

Other Websites

Biomedical Sciences Graduate Program

Gladstone Institute of Neurological Disease