Mechanisms of Neuronal Death in Huntington’s Disease

Abstract

Huntington’s disease (HD) is an inherited, progressive, and always fatal, neurodegenerative disorder characterized by degeneration of neurons in the striatum and cerebral cortex, which results in involuntary motor movements. HD is one of several neurodegenerative diseases found to be caused by an expansion of CAG repeats encoding glutamine in specific proteins. The gene affected in HD is located on chromosome 4p and encodes a 3144 amino acid protein called huntingtin (Huntington’s Disease Collaborative Research Group, 1993). Other diseases known to be caused by CAG repeat expansions of greater than 35 repeats include spinal cerebellar ataxia (CAG repeat expansion in genes SCA1, SCA2, SCA3, SCA6, and SCA7), spinobulbar muscular atrophy (CAG repeat expansion in AR), and dentato-rubro-pallido-luyisian atrophy (DRPLA gene). These conditions are a subset of a larger class of diseases (Fragile X syndrome, Friederich’s ataxia, and myotonic dystrophy) associated with expansion of trinucleotide repeats either in coding or in noncoding regions of the DNA. Glutamine repeat (polyglutamine) diseases are the only trinucleotide expansion diseases in which triplet repeat expansion occurs within the coding DNA region, thus leading to protein changes. It is expected that the list of these diseases, all of which target excitable tissues in the human body (nerve and muscle cells), will grow in the coming years.