Measuring neuron specific striatal synaptic proteomes to determine the mechanism of selective neurodegeneration in HD

Project: Research project

Description

The goal of the proposed research is to advance our understanding of the mechanisms responsible for impaired synaptic communication in Huntington’s disease (HD). HD is characterized by hyperactive dyskinesia that causes robust involuntary movements referred to as Huntington’s chorea. However, in the advanced stages of disease, pathology transitions to a state of hypoactivity and patient movements become slow and rigid. Striatal dysfunction in HD brain is a major driver of pathology and responsible for impaired motor function. In this research proposal, we aim to determine the molecular mechanisms responsible for impaired communication in the in the striatal indirect pathway (e.g. striatum to globus pallidus). Indirect pathway medium spiny neurons (iMSNs) in the striatum send axons to two distinct types of cells in the globus pallidus known as prototypic and arkypallidal neurons. Recent findings from the Surmeir lab show that synaptic dysfunction in striatal / globus pallidal synapses may play a key role in motor dysfunction in HD. These electrophysiological findings suggest that impairment of prototypic and arkypallidal synapses are not equally affected. In this research, we will use our custom synaptic probes, cell specific expression and quantitative mass spectrometry-based proteomic analysis to quantitatively compare prototypic and arkypallidal postsynaptic proteomes in the HD-model and control mouse brains.
StatusActive
Effective start/end date8/1/187/31/20

Funding

  • CHDI Foundation, Inc. (AGMT 8/20/18)

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Corpus Striatum
Huntington Disease
Proteome
Neurons
Globus Pallidus
Dyskinesias
Synapses
Communication
Pathology
Brain
Research
Proteomics
Axons
Mass Spectrometry
Research Design