Project Summary
Parkinson’s disease (PD) is the most common motor neurodegenerative disease and, as one of the
fastest growing neurological disorders in prevalence, disability-adjusted life years, and deaths, an increasingly
significant public health issue. Its core motor symptoms are caused by the dysfunction and death of dopamine
(DA) neurons in the Substantia Nigra pars compacta (SNpc). These neurons are particularly vulnerable, and
understanding the molecular underpinnings of this enhanced vulnerability may be critical for developing disease-
modifying treatments. Due to the irreversible nature of neurodegeneration, neuroprotective therapies are likely
to be most effective when targeting early, more reversible forms of neuronal dysfunction. In PD, one such early
pathological feature is the degeneration of SNpc DA neuron axons, which are lost earlier than the cell bodies
and whose degeneration more closely correlates with the decline of efficacy of dopamine replacement therapy
(the primary symptomatic treatment for PD). Because axon loss may be targeted prior to cell death, identifying
its mechanisms may be essential for developing neuroprotective therapies.
Prior work indicates that axonal mitochondria are dynamically regulated and specialized to support axonal
function and survival. In this proposal, I seek to identify mechanisms by which axonal mitochondria are
specialized to promote the function and survival of SNpc DA neuron axons, and to identify how
alterations in these processes may contribute to PD pathophysiology. In Aim 1, I will develop a novel
molecular labeling and volumetric imaging platform for characterizing baseline features of mitochondria in the
axons of SNpc DA neurons, such as their density across different striatal subregions, and quantify their spatial
relationship to presynaptic structures. In Aim 2, I will implement an immunopurification strategy (Mitotag) for
separately isolating axonal and somatodendritic mitochondria from SNpc DA neurons, and carry out proteomics
and functional assays to identify the molecular and functional specialization of axonal mitochondria. In Aim 3, I
will then carry out similar experiments in a viral PD mouse model to identify how alterations to axonal
mitochondria may contribute to axonal degeneration. Using these findings as a guide, I will then carry out
overexpression or knockdown experiments to evaluate whether rescuing axonal mitochondrial defects could
alleviate axonal degeneration in PD.
By delving into the fundamental biology of how mitochondria are specialized to sustain axonal survival
and probing how their functions are perturbed in disease, this proposal will help shed light into basic principles
of neuronal maintenance and function while potentially identifying early mechanisms of disease that can be
targeted before irreversible cell death.
