Title: The Molecular Pathology of Huntingtons Disease (HD)
Volume: 3
Issue: 4
Author(s): David C. Rubinsztein
Affiliation:
Keywords:
Huntington, oxygen, mitochondrial, antibodies
Abstract: Huntingtons disease (HD) is one of nine known neurodegenerative conditions caused by CAG trinucleotide repeat expansions that are translated into abnormally long polyglutamine tracts in the mutant protein. This review describes the clinical and pathological features of HD and considers the genetic and transgenic / knockout mouse data supporting gain-of-function vs. loss-of-function mechanisms whereby the mutation may cause disease. Intraneuronal aggregates (also known as inclusions) are one of the pathological hallmarks of all of the polyglutamine expansion diseases. A major focus of the review is a detailed consideration of the debate as to whether aggregates / aggregation are pathogenic, deleterious or epiphenomena, drawing on data from cell-based and animal models of different polyglutamine diseases and also from the polyalanine codon reiteration disease, oculopharyngeal muscular dystrophy, which manifests intramuscular nuclear inclusions. I will describe how cells deal with aggregateprone and misfolded proteins using chaperones and various degradation pathways. Using data from animal and cell-based models, the review considers some of the different but non-mutually exclusive mechanisms whereby the HD mutation may cause disease, including early changes in gene transcription, production of reactive oxygen species, aberrant proteinprotein interactions and abnormal cellular susceptibility to glutamate. Understanding possible pathogenic mechanisms for HD has provided a rational basis for intervention strategies, ranging from antibodies / peptides that prevent mutant protein aggregation to drugs that enhance mitochondrial function and protect against excitotoxicity.
