Neurodegenerative disorders such as Huntington’s disease and spinocerebellar ataxias (SCAs) are characterized by proteins with expanded polyglutamine (polyQ) regions—long stretches of the amino acid glutamine. The accumulation of misfolded polyQ proteins impairs neuronal functions, but the underlying molecular mechanisms are unclear.

Researchers show that coiled-coil structures in polyQ regions of SCA type 3 (SCA3) proteins contribute to neuronal toxicity and behavioral abnormalities in fruit flies. The authors generated transgenic fruit fly lines expressing three structural variants of SCA3 polyQ proteins.

Sensory neurons expressing the variant without coiled-coil structures showed no abnormalities in neuronal extensions called dendrites. By contrast, neurons expressing the two variants with coiled-coil structures exhibited various dendrite defects. Moreover, fly larvae expressing SCA3 variants with coiled-coil structures displayed movement abnormalities, such as increased head turning.

Increasing levels of the Foxo protein, which interacts with SCA3 polyQ proteins, reduced dendrite and motility defects induced by coiled-coil structures in sensory neurons and larvae. Taken together, interactions between Foxo and polyQ proteins containing coiled-coil structures may mediate neuronal and behavioral defects in fruit flies.

According to the authors, the study suggests that inhibiting polyQ-Foxo interactions might be a viable therapeutic strategy for polyQ diseases.