Apoptosis in Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, fatal disorder. Patients display increasing motor, psychiatric and cognitive impairment and at autopsy, late-stage patient brains show extensive striatal (caudate and putamen), pallidal and cortical atrophy. The initial and primary target of degeneration in HD is the striatal medium spiny GABAergic neuron, and by end stages of the disease up to 95% of these neurons are lost [J. Neuropathol. Exp. Neurol. 57 (1998) 369]. The disease is caused by an elongation of a polyglutamine tract in the N-terminal of the huntingtin gene, but it is not known how this mutation leads to such extensive, but selective, cell death [Cell 72 (1993) 971]. There is substantial evidence from in vitro studies that connects apoptotic pathways and apoptosis with the mutant protein, and theories linking apoptosis to neuronal death in HD have existed for several years. Despite this, evidence of apoptotic neuronal death in HD is scarce. It may be that the processes involved in apoptosis, rather than apoptosis per se, are more important for HD pathogenesis. Upregulation of the proapoptotic proteins could lead to cleavage of huntingtin and as recent data has shown, the consequent toxic fragment may itself elicit toxic effects on the cell by disrupting transcription. In addition, the increased levels of proapoptotic proteins could contribute to slowly developing cell death in HD, selective for the striatal medium spiny GABAergic neurons and later spreading to other areas. Here we review the evidence supporting these mechanisms of pathogenesis in HD.