Huntington's disease (HD) is a dominantly inherited and incurable neurodegenerative disorder. Although the ultimate fate, and hallmark, of HD is selective neurodegeneration in striatum and cortex, emerging evidence suggests that corticostriatal synaptic dysfunction and degradation precedes neuron death and causes early HD symptoms. However, it is not known how mutant Huntingtin (mHtt) damages corticostriatal synapses. The goal of the proposed research is to address this deficit and to identify druggable targets by delineating the molecular cascade causing loss of post-synaptic elements (spines) on striatal medium spiny neurons (MSNs), the primary cell type affected in HD. This will be accomplished by investigating pathology in a recently developed in vitro model with functional corticostriatal circuitry and age-dependent loss of MSN spines in mHtt-expressing cultures. Molecules contributing to mHtt-induced synapse loss will be genetically deleted in the striatum of HD mice to validate potential targets by rescue of disease progression. As mHtt binds to and increases the activity of an ion channel in the endoplasmic reticulum (ER), this depletes calcium from the ER, which consequentially activates ion channels in the plasma membrane through a process known as store-operated calcium entry. This is excessive in mHtt-expressing neurons, contributing to neurodegeneration and HD progression in a fruit fly HD model.
The aim of the proposed research is to identify the molecular components of the store-operated calcium entry pathway in MSN spines and to test their role in the pathogenesis and progression of HD.
Aim 1 is to determine which stromal interaction molecule induces mHtt-dependent store-operated calcium entry in MSN spines.
Aim 2 is to identify the ion channel mediating mHtt-dependent calcium influx in MSN spines.
Aim 3 is to identify calcium-sensitive molecules that drive MSN spine loss. The proposed experiments will elucidate how mHtt damages synapses in HD, leading to disease-modifying HD treatments.

Public Health Relevance

Huntington's disease (HD) is a dominantly inherited, incurable neurodegenerative disease that begins in midlife and ultimately results in death. HD affects ~30,000 Americans and ~150,000 more are at risk of inheriting the HD gene mutation, creating significant implications for public health. We will investigate synaptic dysfunction in the corticostriatal circuit, a key locus of HD pathology, with the goal of identifying key molecular targets in the pathogenesis of HD in order to develop rational treatments for the disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Miller, Daniel L
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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