Neuroscience Graduate Program at UCSF
Mitochondrial Biology in Neurodegenerative Disease
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).
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.
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.
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.
Why are substantia nigra DA neurons intrinsically vulnerable to mitochondrial stressors?
How do PD proteins disrupt mitochondrial function and produce neurodegeneration?
How do changes in energy metabolism contribute to the pathogenesis of AD?
What are the mechanisms by which mitochondrial dynamics influence neurodegeneration?
How and why are mitochondria turned over?
Bryce Mendelsohn, MD, PhD, Postdoctoral Fellow
Dominik Haddad, PhD, Postdoctoral Fellow
Huihui Li, PhD, Postdoctoral Fellow
Max Darch, PhD, Postdoctoral Fellow
Katharine Yu, Research Associate
Lauren Shields, Graduate Student
Haddad H, Nakamura K. (2015) Understanding the susceptibility of dopamine neurons to mitochondrial stressors in Parkinson’s disease. FEBS Letters.
Pathak D, Shields L, Mendelsohn BA, Haddad D, Lin W, Gerencser AA, Kim H, Brand MD, Edwards RH, Nakamura K. (2015) The role of mitochondrially derived ATP in synapatic vesicle recycling. J Biol Chem. 290(37):22325-36. (paper of the week)
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. (2015) Dynamin-related protein 1 (Drp1) is required for normal mitochondrial bioenergetic and synaptic function in CA1 hippocampal neurons. Cell Death Dis. 6:e1725
Berthet A, Margolis EB, Zhang J, Hsieh I, Zhang J, Hnasko T, Ahmad J, Edwards RH, Sesaki H, Huang EJ, Nakamura K. (2014) Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons. J Neuroscience. 34(43):14304-14317.
Skibinski G, Nakamura K, Cookson MR, 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.
Pathak D, Berthet A, Nakamura K. (2013) Energy failure- does it contribute to neurodegeneration? Ann Neurol. 74(4), 506-516.
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)
Nakamura, K. (2013) α-Synuclein and mitochondria: partners in crime? Neurotherapeutics. 10(3), 391-9.
Itoh K, Nakamura K, Iijima M, Sesaki H. Mitochondrial Dynamics in Neurodegeneration. (2013) 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, Edwards RH. (2011) Direct membrane association drives mitochondrial fission by the Parkinson’s disease-associated protein α-synuclein. J Biol Chem. 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.
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, 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, Edwards RH. (2007) Physiology versus pathology in Parkinson's disease. Proc Natl Acad Sci USA. 104(29), 11867-8.
Nakamura K, Aminoff MJ. (2007) Huntington’s disease: clinical characteristics, pathogenesis and therapies. Drugs Today. 43(2), 97-116.
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.
Ken Nakamura, M.D./Ph.D.
UCSF MC 1230
Gladstone Institute of Neurological Disease
1650 Owens Street, room 308
San Francisco, CA 94158