Expression of polyglutamine repeats at the pathogenic threshold modestly enhances tau neurotoxicity and protein accumulation in C. elegans.

Abstract

CAG repeat expansions within the HTT gene cause Huntington's disease (HD), a devastating neurodegenerative disease characterized by progressive movement, cognitive, and behavioral symptoms. These expansions result in the expression and accumulation of neurotoxic poly-glutamine (polyQ). Disease initiation depends on the length of the expansion, with fewer than 35 repeats of polyQ typically not pathogenic, while 40 or greater repeats almost always result in HD. Longer expansions correlate with earlier onset of disease; however, there may be other factors that contribute to disease initiation or progression, particularly in individuals with repeat lengths close to or below the 40 repeat length pathogenic threshold. Aggregates of the protein tau are a frequent co-pathology in HD and may modify disease presentation. To examine relationships between tau and polyQ in vivo , we generated C. elegans co-expressing 40 repeats of polyQ (polyQ(40)) and human tau pan-neuronally. We found that co-expression of tau and polyQ(40) results in mild worsening of motility defects and increased accumulation of total and phosphorylated tau but not polyQ. These results suggest that co-morbid tau and polyQ can worsen neuronal dysfunction, and the presence of tau pathology may contribute to disease phenotypes in patients with HD, particularly individuals with repeat lengths close to the pathogenic threshold.