2013 Scientific Report

Van Andel Research Institute | Scientific Report
Huntington’s disease (HD) is an adult-onset neurodegenerative disorder characterized by motor dysfunction, cognitive deficits,
and neuropsychiatric abnormalities. Disease onset typically occurs between the ages of 35 and 55 and progresses inevitably
to death approximately 15 years later. The disease is caused by a trinucleotide CAG repeat expansion in the HD gene, which
codes for the protein huntingtin (HTT). The CAG repeat sequence is translated into a polyglutamine tract in the HTT protein,
and thus HD belongs to a group of at least nine polyglutamine toxicity disorders. Interestingly, while the size of the CAG repeat
is polymorphic in unaffected individuals (ranging from 9 to 35 repeats), the disease range begins at precisely 35 CAG repeats,
and the severity of the disease is correlated with the length of the repeat.
Both worms and mouse models of HD have been created through transgenic expression of varying lengths of the huntingtin
protein with a disease-length polyglutamine tract. The worm models express the mutant polyglutamine sequence either in
body wall muscle or in neurons. These worms exhibit numerous abnormal phenotypes—including decreased life span, slow
development, and decreased mobility—that are not observed in worms expressing a normal length repeat. Mouse models of
HD have been shown to recapitulate almost all features of human HD, including motor deficits, cognitive deficits, and selective
neurodegeneration.
Our project examines 1) whether genes that increase life span will be beneficial in worm models of HD (i.e., will the increased
longevity imparted by the aging gene reduce the severity of the polyglutamine toxicity phenotypes?), and 2) whether specific
changes that take place during normal aging and that have been implicated in neurodegenerative disease contribute to pathogenesis
in worm models of HD (i.e., do the higher levels of oxidative stress in older individuals contribute to pathogenesis?).
Both of these objectives are being studied using two complementary approaches: genetic crosses to generate double mutants,
and specific knockdown of gene expression using RNAi. The results from the worm screen will be used to prioritize the genes
that will be studied in mouse models, which provide more physiologically accurate models of HD.
Similar experiments are being conducted in animal models of Parkinson’s disease. By comparing the results, it will be possible
to identify both overlapping and disease-specific mechanisms in these two neurodegenerative disorders.
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