Developmental origins of Huntington's disease
Arteaga Bracho, Eduardo Esteban
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Huntington's disease (HD) is a fatal inherited neurodegenerative disorder that is clinically characterized by movement abnormalities and psychiatric alterations appearing during midlife. The causative gene of HD, mutant huntingtin (mHtt), is expressed from the beginning of embryogenesis in most cells of the body and throughout life. Recent studies have shown that mHtt impairs germline formation, neural induction, neurogenesis in different stem cell niches as well as the assembly and functioning of neuronal circuitries. In addition, similar developmental alterations have been observed in the absence or with the presence of low levels of the wild-type huntingtin (wHtt), suggesting that a loss of function mechanism partially explains mHt- associated developmental abnormalities.;The primary goal of this thesis is to determine whether mHtt-associated developmental abnormalities contribute to the clinical manifestations of HD. To address this, I employed different transgenic mouse models to temporally control the expression of the mHtt or wHtt gene during embryonic development, and these HD mouse models were examined using multiple behavioral, pathological and electrophysiological paradigms. I demonstrate that that mHtt-associated developmental defects are sufficient to cause the most prominent clinical manifestations in Chapter 2, where I expressed mutant huntingtin exclusively during development in a HD mouse model and observed motor abnormalities, neuronal degeneration, firing impairments of different cells types, and alterations in the communication between the cortex and the striatum, two brain structures closely associated with the disease phenotype in HD. In Chapter 3, I demonstrated that selective expression of low levels of wHtt during development are also able to produce neurological abnormalities, neuronal degeneration and myelin abnormalities in both the striatum and deep layers of the motor cortices which are pathological specific impairments associated with HD.;I conclude that mHtt-associated developmental abnormalities are an essential component of the pathogenesis of Huntington's disease and contribute to the progression of the disorder. These developmental abnormalities are, in part, explained by a loss of function mechanism. My findings suggest that development serves as a seminal time window to help discover the mechanisms underlying Huntington's disease, and to design innovative therapeutic strategies to ameliorate or even cure this fatal neurodegenerative disorder.