Chapter 45 – Cellular and Molecular Mechanisms of Neuronal Dysfunction in Huntington's Disease

Huntington's disease (HD) is the most frequent neurodegenerative disease caused by an expansion of polyglutamines (CAG). The main clinical manifestations of HD are chorea, cognitive, and psychiatric impairments. The transmission of HD is autosomal dominant with a complete penetrance. HD has a single genetic cause, a well-defined neuropathology, and informative premanifest genetic testing of the disease is available. Striatal atrophy begins as early as 15 years before disease onset and continues throughout the period of manifest illness. One important characteristic of HD is the striatal vulnerability, despite similar expression of the protein in other brain areas. Aggregation of the mutated Huntingtin (HTT), excitotoxicity, mitochondrial dysfunctions and energy deficits, alteration of cholesterol metabolism along with transcriptional dysregulation are all part of the cellular events that underlie neuronal dysfunction. Among these nonexclusive mechanisms, an alteration of cortico-striatal signaling is thought to orchestrate the downstream events involved in the cascade of striatal dysfunction.