Ken Nakamura’s lab studies mitochondria, the “power centers” inside each cell that convert nutrients into ATP, a form of energy the cell can use. The lab has two broad, intertwined objectives. The first is to understand how mitochondria and energy metabolism normally support the function of healthy brain neurons. The second is to understand how disruptions in mitochondrial function and metabolism contribute to neurodegenerative diseases, especially Parkinson’s disease, Alzheimer’s disease, and mitochondrial disorders, and to use these insights to develop new therapeutic approaches that boost energy levels in vulnerable cells.
Areas of Expertise
Neurons have long been known to rely heavily on mitochondrial energy production, but scientists have lacked the tools to understand the mechanisms of this dependence. Nakamura’s lab has developed tools to monitor ATP production and study metabolism in normal and diseased neurons, and used them to show that energy failure can result from an imbalance between excessive energy consumption due to increased neural activity and insufficient production. They have also developed cutting-edge approaches to track the fates of individual mitochondria in neurons over time, and used them to make important discoveries about the mitochondrial life cycle in neurons and how it is disrupted in Parkinson’s disease.
Nakamura’s group also provided the first comprehensive map of mitochondrial genes and pathways that maintain cellular energy levels. ATP is the central energy carrier, but the pathways that regulate ATP levels are not systematically understood. The team’s studies provide insight into which diseases may act through energy failure and identify new therapeutic strategies to correct energy failure in these diseases.
Assistant Investigator, Gladstone Institutes
Associate Professor of Neurology, UC San Francisco
Ken Nakamura is an assistant investigator at Gladstone Institutes, and an associate professor of Neurology at UC San Francisco (UCSF). Nakamura earned his bachelor’s degree in chemistry and biological sciences from Cornell University, and his MD and PhD in neurobiology from the University of Chicago, Pritzker School of Medicine. His thesis work in the laboratory of Un Kang focused on the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. He then completed an internship in internal medicine and neurology residency at UCSF, and a subsequent clinical fellowship in movement disorders at UCSF, where he continues to treat patients. Nakamura also completed a postdoctoral fellowship with Robert Edwards at UCSF, investigating the role of a small protein named alpha-synuclein in the development of Parkinson’s disease. His long term goal is to understand how and why neurodegenerative diseases lead to the death of selective neuronal populations, and to develop new therapeutic strategies to treat them.
Why Are You Dedicated to Discovery?
“Clinical trials attempting to modify Parkinson’s progression have all failed so far because we didn’t have a good enough basic science understanding of why the disease occurs; we need to develop that understanding to find effective therapies.”
Honors and Awards
2016 Jon Stolk Award in Movement Disorders for Young Investigators, American Academy of Neurology
2008 Burroughs Wellcome Fund Career Award for Medical Scientists
2001 Steven Lukes Memorial Prize, University of Chicago
1999 American Academy of Neurology Extended Neuroscience Award
- A high-throughput screen of real-time ATP levels in individual cells reveals mechanisms of energy failure. Mendelsohn BA, Bennett NK, Darch MA, Yu K, Nguyen MK, Pucciarelli D, Nelson M, Horlbeck MA, Gilbert LA, Hyun W, Kampmann M, Nakamura JL, Nakamura K. PLoS Biol. 2018 08; 16(8):e2004624.
- Mapping the Genetic Landscape of Human Cells. Horlbeck MA, Xu A, Wang M, Bennett NK, Park CY, Bogdanoff D, Adamson B, Chow ED, Kampmann M, Peterson TR, Nakamura K, Fischbach MA, Weissman JS, Gilbert LA. Cell. 2018 08 09; 174(4):953-967.e22.
- A Map of Human Mitochondrial Protein Interactions Linked to Neurodegeneration Reveals New Mechanisms of Redox Homeostasis and NF-?B Signaling. Malty RH, Aoki H, Kumar A, Phanse S, Amin S, Zhang Q, Minic Z, Goebels F, Musso G, Wu Z, Abou-Tok H, Meyer M, Deineko V, Kassir S, Sidhu V, Jessulat M, Scott NE, Xiong X, Vlasblom J, Prasad B, Foster LJ, Alberio T, Garavaglia B, Yu H, Bader GD, Nakamura K, Parkinson J, Babu M. Cell Syst. 2017 12 27; 5(6):564-577.e12.
- Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson's disease. Haddad D, Nakamura K. FEBS Lett. 2015 Dec 21; 589(24 Pt A):3702-13.
- The role of mitochondrially derived ATP in synaptic vesicle recycling. Pathak D, Shields LY, Mendelsohn BA, Haddad D, Lin W, Gerencser AA, Kim H, Brand MD, Edwards RH, Nakamura K. J Biol Chem. 2015 Sep 11; 290(37):22325-36.
- Dynamin-related protein 1 is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons. Shields LY, Kim H, Zhu L, Haddad D, Berthet A, Pathak D, Lam M, Ponnusamy R, Diaz-Ramirez LG, Gill TM, Sesaki H, Mucke L, Nakamura K. Cell Death Dis. 2015 Apr 16; 6:e1725.
- Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. Berthet A, Margolis EB, Zhang J, Hsieh I, Zhang J, Hnasko TS, Ahmad J, Edwards RH, Sesaki H, Huang EJ, Nakamura K. J Neurosci. 2014 Oct 22; 34(43):14304-17.
- Mutant LRRK2 toxicity in neurons depends on LRRK2 levels and synuclein but not kinase activity or inclusion bodies. Skibinski G, Nakamura K, Cookson MR, Finkbeiner S. J Neurosci. 2014 Jan 08; 34(2):418-33.
- SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK. Ho L, Titus AS, Banerjee KK, George S, Lin W, Deota S, Saha AK, Nakamura K, Gut P, Verdin E, Kolthur-Seetharam U. Aging (Albany NY). 2013 Nov; 5(11):835-49.
- Energy failure: does it contribute to neurodegeneration? Pathak D, Berthet A, Nakamura K. Ann Neurol. 2013 Oct; 74(4):506-16.
- The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Manzanillo PS, Ayres JS, Watson RO, Collins AC, Souza G, Rae CS, Schneider DS, Nakamura K, Shiloh MU, Cox JS. Nature. 2013 Sep 26; 501(7468):512-6.
- A neo-substrate that amplifies catalytic activity of parkinson's-disease-related kinase PINK1. Hertz NT, Berthet A, Sos ML, Thorn KS, Burlingame AL, Nakamura K, Shokat KM. Cell. 2013 Aug 15; 154(4):737-47.
- a-Synuclein and mitochondria: partners in crime? Nakamura K. Neurotherapeutics. 2013 Jul; 10(3):391-9.
- Molecular chaperone TRAP1 regulates a metabolic switch between mitochondrial respiration and aerobic glycolysis. Yoshida S, Tsutsumi S, Muhlebach G, Sourbier C, Lee MJ, Lee S, Vartholomaiou E, Tatokoro 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. Proc Natl Acad Sci U S A. 2013 Apr 23; 110(17):E1604-12.
- Mitochondrial dynamics in neurodegeneration. Itoh K, Nakamura K, Iijima M, Sesaki H. Trends Cell Biol. 2013 Feb; 23(2):64-71.
- Direct membrane association drives mitochondrial fission by the Parkinson disease-associated protein alpha-synuclein. 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. J Biol Chem. 2011 Jun 10; 286(23):20710-26.
- Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH. Neuron. 2010 Jan 14; 65(1):66-79.
- The behavior of alpha-synuclein in neurons. Fortin DL, Nemani VM, Nakamura K, Edwards RH. Mov Disord. 2010; 25 Suppl 1:S21-6.
- Optical reporters for the conformation of alpha-synuclein reveal a specific interaction with mitochondria. Nakamura K, Nemani VM, Wallender EK, Kaehlcke K, Ott M, Edwards RH. J Neurosci. 2008 Nov 19; 28(47):12305-17.
- Effects of unilateral subthalamic and pallidal deep brain stimulation on fine motor functions in Parkinson's disease. Nakamura K, Christine CW, Starr PA, Marks WJ. Mov Disord. 2007 Apr 15; 22(5):619-26.
- Huntington's disease: clinical characteristics, pathogenesis and therapies. Nakamura K, Aminoff MJ. Drugs Today (Barc). 2007 Feb; 43(2):97-116.
- Textbook of neural repair and rehabilitation (eds Selzer ME, Cohen L, Gage FH, Clarke S and Duncan PW) Nakamura K Kang UJ. . Trophic factor delivery by gene therapy. 2006; 532-547.
- Lipid rafts mediate the synaptic localization of alpha-synuclein. Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH. J Neurosci. 2004 Jul 28; 24(30):6715-23.
- Vitamin B12 deficiency. Nakamura K, Mukherjee P, Swanson RA. Arch Neurol. 2004 Jun; 61(6):960.
- Polyneuropathy following gastric bypass surgery. Nakamura K, Roberson ED, Reilly LG, Tsao JW. Am J Med. 2003 Dec 01; 115(8):679-80.
- Potential of gene therapy for pediatric neurotransmitter diseases: lessons from Parkinson's disease. Kang UJ, Nakamura K. Ann Neurol. 2003; 54 Suppl 6:S103-9.
- The localization and functional contribution of striatal aromatic L-amino acid decarboxylase to L-3,4-dihydroxyphenylalanine decarboxylation in rodent parkinsonian models. Nakamura K, Ahmed M, Barr E, Leiden JM, Kang UJ. Cell Transplant. 2000 Sep-Oct; 9(5):567-76.
- Preferential resistance of dopaminergic neurons to glutathione depletion in a reconstituted nigrostriatal system. Nakamura K, Won L, Heller A, Kang UJ. Brain Res. 2000 Aug 11; 873(2):203-11.
- The selective toxicity of 1-methyl-4-phenylpyridinium to dopaminergic neurons: the role of mitochondrial complex I and reactive oxygen species revisited. Nakamura K, Bindokas VP, Marks JD, Wright DA, Frim DM, Miller RJ, Kang UJ. Mol Pharmacol. 2000 Aug; 58(2):271-8.
- Preferential resistance of dopaminergic neurons to the toxicity of glutathione depletion is independent of cellular glutathione peroxidase and is mediated by tetrahydrobiopterin. Nakamura K, Wright DA, Wiatr T, Kowlessur D, Milstien S, Lei XG, Kang UJ. J Neurochem. 2000 Jun; 74(6):2305-14.
- The role of glutathione in dopaminergic neuronal survival. Nakamura K, Wang W, Kang UJ. J Neurochem. 1997 Nov; 69(5):1850-8.