Neuronal vulnerability in Huntington’s disease

Abstract

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by the expansion of polyglutamine encoding CAG repeats over 40 in exon 1 of the HTT gene. The expanded repeats encode a mutant huntingtin (mHTT) protein which mediates most of the pathogenic mechanisms in HD. It is a fatal disease and its symptoms range from motor, cognitive and psychiatric dysfunctions. Despite the ubiquitous distribution of mHTT, neuronal cells are preferentially affected, particularly striatal cells. In this review, cell autonomous and non-cell autonomous factors contributing to striatal vulnerability will be discussed to determine which has the greatest impact. Non-cell autonomous factors include; aggregation, altered pathways, mitochondrial dysfunction and huntingtin interacting proteins. Meanwhile, cell autonomous factors encompass dysregulated gene expression and unstable somatic expansions. Collectively, it seems that mHTT mediates most of the toxic aspects observed in HD in parallel with stripped neuroprotective factors preserving neuronal integrity. In conclusion, no single cause can be pinpointed in regard to striatal vulnerability.