Huntington's disease: the case for genetic modifiers

Abstract

For almost three decades, Huntington's disease has been a prototype for the application of genetic strategies to human disease. HD, the Huntington's disease gene, was the first autosomal defect mapped using only DNA markers, a finding in 1983 that helped to spur similar studies in many other disorders and contributed to the concept of the human genome project. The search for the genetic defect itself pioneered many mapping and gene-finding technologies, and culminated in the identification of the HD gene, its mutation and its novel protein product in 1993. Since that time, extensive investigations into the pathogenic mechanism have utilized the knowledge of the disease gene and its defect but, with notable exceptions, have rarely relied for guidance on the genetic findings in human patients to interpret the relevance of findings in non-human model systems. However, the human patient still has much to teach us through a detailed analysis of genotype and phenotype. Such studies have implicated the existence of genetic modifiers - genes whose natural polymorphic variation contributes to altering the development of Huntington's disease symptoms. The search for these modifiers, much as the search for the HD gene did in the past, offers to open new entrées into the process of Huntington's disease pathogenesis by unlocking the biochemical changes that occur many years before diagnosis, and thereby providing validated target proteins and pathways for development of rational therapeutic interventions.

Chemical and Biological Approaches for Adapting Proteostasis to Ameliorate Protein Misfolding and Aggregation Diseases-Progress and Prognosis

“…Huntington's disease is caused by expansion of a contiguous polyglutamine tract in exon 1 of the huntingtin protein (Gusella and MacDonald 2009). When the polyglutamine expansion exceeds a threshold length of about 40 residues, aggregation and neurotoxicity can occur, with an age of onset that roughly inversely correlates with the length of the polyglutamine repeat in humans and organismal models.…”

“…A plethora of evidence suggests that the accumulation of aggregated proteins in the cytosol appears to cause degenerative diseases, including Huntington's disease and Parkinson's disease, among many others (Selkoe 2004;Gusella and MacDonald 2009). Thus, a recent paper demonstrating activation of the proteasome through USP14 small molecule inhibition represents a promising strategy to clear aggregated proteins and potentially ameliorate these maladies (Lee et al 2010).…”

Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes

“…[11][12][13] A number of processes were implicated in early disease pathogenesis; however, specific genetic modifiers are still under investigation. 14 Support for the hypothesis that genetic background may modulate the CAG mutation rate has recently been shown at a population level. 15 In a 2011 study by Warby et al 15 , differences in HD prevalence rates reported in European and Asian populations were associated with different haplotype distributions of disease alleles.…”

The minus of a plus is a minus. Mass death of selected neuron populations in sporadic late-onset neurodegenerative disease may be due to a combination of subtly decreased capacity to repair oxidative DNA damage and increased propensity for damage-related apoptosis

“…Some of the familial forms of amyotrophic lateral sclerosis (ALS1, associated with mutations in the SOD1 gene) and the relatively rare Huntington's disease (HD, due to pathological expansion of a CAG repeat in the HTT gene) are transmitted in an autosomal dominant fashion with virtually complete penetrance, although the age of onset may vary significantly even among patients with the same mutation, suggesting the existence of modulating factors. [6,7] Most LONDDs, including AD and PD, however, are believed to have a multifactorial genesis, as 70%À90% of all cases are sporadic and age-matched asymptomatic carriers of known disease-associated mutations have been described. [8,9] No single environmental factor has been yet implicated as a factor in the pathogenesis of sporadic LONDD with any degree of certainty.…”