UC San Diego

Huntington’s disease is a debilitating autosomal dominant neurological condition which causes neural degradation and psychological and motor degradation depending on the severity of the expansion of a trinucleotide repeat responsible for its symptoms. Studies have found that longer expansions of the trinucleotide repeat correlate with earlier onset of the symptoms of HD; with very long expansions, the symptoms can appear as early as childhood. Symptoms of HD include conditions such as motor and cognitive dysfunction, loss of daily living capacity, weight loss, increased risk of death, whose severity have been found to be associated with the length of the CAG trinucleotide expansion. HD also causes repeat-number associated physical degeneration of brain tissue in areas such as the cortex, putamen, striatum, and various others. While many studies have been conducted on JHD in animal and cell models, few studies have analyzed the disruption to the proteome in human JHD brains. In this project, we determined the number of CAG trinucleotide repeat numbers and investigated the dysregulation of the proteome in the BA4, BA6 cortex and putamen of JHD brains compared to age-matched control brains, as well as curating a database of Htt-interacting proteins from animal studies which allowed us to determine which of the dysregulated proteins are Htt-interacting and are likely the first suspects in the many protein network disruptions observed in JHD. We found that there are significant protein network disruptions in the mitochondria, translation and RNA processing, and cellular transport functions, as well as various others.