Polyglutamine disease: from pathogenesis to therapy.
Polyglutamine diseases are inherited neurodegenerative conditions arising from expanded trinucleotide CAG repeats in the disease-causing gene, which are translated into polyglutamine tracts in the resultant protein. Although these diseases share a common type of mutation, emerging evidence suggests that pathogenesis is complex, involving disruption of key cellular pathways, and varying with the disease context.  An understanding of polyglutamine disease mechanisms is critical for development of novel therapeutics. Here we summarise theories of molecular pathogenesis, and examine ways in which this knowledge is being harnessed for therapy, with reference to work under way at the University of Cape Town. Despite a plethora of preclinical data, clinical trials of therapies for polyglutamine diseases have had only limited success. However, recently initiated trials, including those using gene silencing approaches, should provide valuable insights into the safety and efficacy of therapies directly targeting polyglutamine pathogenesis. This is particularly relevant in the South African context, where the frequencies of two polyglutamine diseases, spinocerebellar ataxia types 1 and 7, are among the highest globally.
Division of Human Genetics, Faculty of Health Sciences, University of Cape Town.
Lauren M
LM
Watson
Janine
J
Scholefield
L Jacquie
LJ
Greenberg
Matthew J A
MJ
Wood
D001343:Autophagy; D020868:Gene Silencing; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D009154:Mutation; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D013019:South Africa; D014158:Transcription, Genetic
D010455:Peptides; C097188:polyglutamine