Ken Nakamura, MD, PhD

Associate Professor
Neurology
415-734-2550

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).

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.

Current Projects

  1. Why are substantia nigra DA neurons intrinsically vulnerable to mitochondrial stressors?
  2. How do PD proteins disrupt mitochondrial function and produce neurodegeneration?
  3. How do changes in energy metabolism contribute to the pathogenesis of AD?
  4. What are the mechanisms by which mitochondrial dynamics influence neurodegeneration?
  5. How and why are mitochondria turned over?
  6. How can we restore or even boost energy levels in cells and will this protect against neurodegeneration?

Lab Members

Max Darch, PhD
Postdoctoral Fellow
max.darch@gladstone.ucsf.edu

Dominik Haddad, PhD
Postdoctoral Fellow
dominik.haddad@gladstone.ucsf.edu

Huihui Li, PhD
Postdoctoral Fellow
huihui.li@gladstone.ucsf.edu

Bryce Mendelsohn, PhD
Postdoctoral Fellow
bryce.mendelsohn@gladstone.ucsf.edu

Kylie Huang
Research Associate
kylie.huang@gladstone.ucsf.edu

Nathan Mercado
Research Associate
nathan.mercado@gladstone.ucsf.edu

Lab Website

Publications: