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Huntington's disease (HD) is an autosomal dominant neurodegenerative condition associated with abnormal movements, cognitive deterioration, and psychiatric symptoms. The causative mutation is a (CAG)n trinucleotide repeat expansion of more than 35 repeats, which is translated into an abnormally long polyglutamine tract in the huntingtin protein. 1 2
HD is a member of a family of neurodegenerative diseases caused by CAG/polyglutamine expansions, which include spinobulbar muscular atrophy (SBMA), spinocerebellar ataxias (SCA) types 1, 2, 3, 6, and 7, and dentatorubral-pallidoluysian atrophy. All diseases are dominantly inherited (except for SBMA, which is X linked). In all cases, age at onset correlates inversely with repeat number. 2 The polyglutamine expansion mutation causes disease by conferring a novel deleterious function on the mutant protein and the severity correlates with increasing CAG repeat number and expression levels in transgenic mice and in cell culture models. 3 4
While each of these diseases is associated with specific regions of neurodegeneration (which in some cases overlap), they are probably caused by similar pathological processes. A hallmark of many of these diseases, including HD, spinobulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxias (SCA) types 1, 2, 3, 6, and 7, is the development of intracellular protein aggregates (inclusions) in the vulnerable neurones. However, the pathogenic role of these aggregates is the subject of vigorous debate. 5
The function of wild type huntingtin is unclear. However, Rigamontiet al 6 recently showed that wild type huntingtin can protect CNS cells from a variety of apoptotic stimuli, including serum withdrawal, stimulation of death receptors, and pro-apoptotic Bcl-2 homologues. We were interested to test if wild type huntingtin protected against the toxicity of polyglutamine expansion mutations. While the experiments in the current paper were in progress, Leavitt et al 7 provided in vivo evidence suggesting that wild type huntingtin can protect against the gain of function mutation caused by the expanded polyglutamine tract in mutant huntingtin, using a YAC transgenic mouse model. This study specifically studied apoptosis in the testis, an organ with very high huntingtin expression. 8 It is relevant to test if these protective effects are seen in other cell types, as the testis may require high levels of huntingtin to protect...