PubMed2001
It is now more than 7 years since the genetic mutation causing Huntington's disease (HD) was first identified. Unstable CAG expansion in the IT15 gene, responsible for disease, is translated into an abnormally long polyglutamine (polyQ) tract near the N-terminus of the huntingtin protein. The presence of expanded polyQ in the mutant protein leads to its abnormal proteolytic cleavage with liberation of toxic N-terminal fragments that tend to aggregate, probably first in the cytoplasm. Subsequent nuclear translocation of the cleaved mutant huntingtin is associated with formation of intranuclear protein aggregates and neurotoxicity, probably involving apoptotic cascades. These processes, which can be experimentally modelled in cultured neuronal and non-neuronal cells, seem to underlie neurodegeneration in HD, and also other polyQ disorders, such as dentatorubro-pallidoluysian degeneration, spinal and bulbar muscular atrophy and the spinocerebellar ataxias. They do not, however, explain why within the corpus striatum and cerebral cortex certain nerve cells are susceptible to disease and others are not. In the human HD brain, vulnerable pyramidal neurones within the deeper layers of the cerebral cortex frequently contain large intranuclear inclusions composed of N-terminal fragments of huntingtin. Such inclusions are, however, rare within neurones of the striatum, even in the medium spiny neurones preferentially lost from this region. While inclusions per se do not seem to be neurotoxic, they may provide a surrogate marker of molecular pathology. Recent studies indicate that the nuclear accumulation of mutant huntingtin interferes with transcriptional events. Of particular importance may be the effect on the genes encoding neurotransmitter receptor proteins, especially those involved with glutamatergic neurotransmission. Such changes may trigger or facilitate a low-grade, chronic excitotoxicity of the glutamatergic cortical projection neurones on their target cells in the striatum, already partly compromised by the toxic effects of the HD mutation. This combination of insults, for anatomical reasons experienced predominantly by striatal projection neurones, would eventually cause their selective demise.