Understanding the Role of Huntingtin in Central Nervous System Development and Function
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2020
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Huntington’s Disease (HD) is a fatal, autosomal dominant disorder caused by a polyglutamine expansion mutation near the N-terminus of the Huntingtin (Htt) gene. Patients with HD experience severe and progressive motor, cognitive, and psychiatric symptoms before succumbing to the disease approximately 15-20 years after disease onset. At the neuropathological level, HD causes the extensive and selective degeneration of striatal projection neurons (SPNs) with the striatum, which are intimately involved in the regulation of voluntary movements. Long thought of as solely a neurodegenerative disease, more recent evidence suggests that both HD symptoms and neurodegeneration are preceded by defects in synaptic connectivity and function. However, how synaptic pathology and neurodegeneration arise in HD remain poorly understood.
The presence of the HD-causing polyglutamine expansion mutation in Htt, along with the well-documented toxicity of mutant Htt (mHtt) to neurons, has led to the widely accepted but not yet proven hypothesis that HD is caused by a toxic gain-of-function of mHtt. However, wildtype Htt is known to play important roles in several cellular processes, suggesting that loss of Htt function, due to a dominant-negative interaction with mHtt, may also contribute to HD pathology. Here, I used the Cre/Lox system to conditionally delete Htt from murine SPNs to investigate the role of Htt in SPNs and to determine whether loss of Htt function can recapitulate aspects of HD. I discovered that loss of Htt in SPNs leads to dysregulated motor function and causes SPNs to degenerate with aging, similar to observations in HD. I also found indications for impaired neuronal health in SPNs lacking Htt long before degeneration occurred. For instance, loss of Htt in SPNs disrupts SPN synaptic connectivity and gene expression, similar to findings in HD patients and mouse models. In sum, my results strongly suggest that Htt is required for SPN health, function, and longevity.
With the importance of Htt in regulating synaptic connectivity well-established, I next investigated how Htt regulates synapse formation at the molecular level, and how this function is impaired when mHtt is present. Specifically, I sought to determine whether mHtt interacts with its pro-synaptogenic binding partner, calcium channel subunit 2-1, to regulate synapse formation. As mice expressing mHtt form too many synapses early in development, I asked whether deleting a copy of 2-1 from mHtt-expressing mice would restore their synapse development to wildtype levels. Indeed, I found that reducing 2-1 in mice expressing mHtt rescued their early synapse development. Taken together, my doctoral dissertation research demonstrates that loss of Htt is sufficient to recapitulate several key features of HD, suggesting that Htt loss-of-function may contribute to HD pathology. My research shows that Htt plays critical roles in maintaining the cellular health and viability of neurons most vulnerable in HD and introduces a potential molecular mechanism underlying Htt’s role in regulating synapse formation and function.
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Lane, Caley (2020). Understanding the Role of Huntingtin in Central Nervous System Development and Function. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/21446.
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