Huntington?s disease (HD) is a progressive genetic disorder with devastating motor and cognitive defects and no therapies to stop or reverse the disease. Monitoring disease progression relies on brain imaging over several months to observe degeneration. Thus, our long-term objective is to identify new peripheral therapeutic targets and biomarkers of HD progression that are easy to access and simple to interpret. Understanding of basic pathophysiological mechanisms in peripheral tissues, such as skeletal muscle, would provide new opportunities for HD therapy and accessible biomarkers. Although classically categorized as a neurodegenerative disease, Both HD patients and mouse models present with debilitating muscle pathology. We previously discovered a loss-of-function in the muscle chloride channel (ClC-1) and inwardly rectifying potassium (Kir) channel in skeletal muscle from transgenic R6/2 Huntington?s disease mice, both contributing to muscle hyperexcitability. The hyperexcitability could help explain rigidity, dystonia, delayed muscle relaxations, and bradykinesia in the disease. We have also shown depressed neuromuscular transmission in late-stage R6/2 mice, which could help explain the motor impersistence in Huntington?s patients. That we found no evidence of denervation supports the possibility that these defects are due to mutant huntingtin expression in muscle. Moreover, the depressed transmission appears to compensate for the muscle hyperexcitability in late- stage R6/2 mice. Therefore, we hypothesis that primary defects in Huntington?s disease skeletal muscle result in compensatory decreases in neuromuscular transmission and motor impersistence. To examine the role of depressed neuromuscular transmission and/or muscle defects in Huntington?s motor symptoms, we will measure force generation in response to nerve and direct muscle stimulation (Aim 1). To assess the role of signaling between nerve and muscle during disease progression, we will compare the time course over which the neuromuscular defects develop to the time course of muscle defects (Aim 2). By developing and examining a muscle-only model of Huntington?s disease, we will determine the role of a primary myopathy in driving muscle and neuromuscular defects (Aim 3). Successfully completing these aims will provide the most complete characterization of general synaptic function in HD to date and further support they hypothesis that HD is also a primary myopathy. By examining the relationship between the muscle and neuromuscular defects in R6/2 mice we will begin to define the role of neuronal and muscle defects in the motor symptoms. Finally, the defects we identify could be targeted by novel therapeutics and will quickly translate to the development of needed peripheral biomarkers of disease progression with collaborators.
We have recently found defects Huntington's disease skeletal muscle that may help explain the motor symptoms of the disease. In this proposal, we will determine if these defects develop within the muscle itself or are a downstream of neurodegeneration. This will help the field better understand the progression of disease symptoms and develop novel therapeutics.
