Selection of Behaviors and Segmental Coordination During Larval Locomotion Is Disrupted by Nuclear Polyglutamine Inclusions in a New Drosophila Huntington's Disease–Like Model

Abstract

: Huntington's disease is an autosomal dominant neurodegenerative disorder that is caused by abnormal expansion of a polyglutamine tract in the huntingtin protein, resulting in intracellular aggregate formation and neurodegeneration. How neuronal cells are affected by such a polyglutamine tract expansion remains obscure. To dissect the ways in which polyglutamine expansion can cause neural dysfunction, the authors generated Drosophila transgenic strains expressing either a nuclear targeted or cytoplasmic form of pathogenic (NHtt-152QNLS, NHtt-152Q), or nonpathogenic (NHtt-18QNLS, NHtt-18Q) N-terminal human huntingtin. These proteins were expressed in the dendritic arborization neurons of the larval peripheral nervous system and their effects on neuronal survival, morphology, and larval locomotion were examined. The authors found that NHtt-152QNLS larvae had altered dendrite morphology and larval locomotion, whereas NHtt-152Q, NHtt-18QNLS, and NHtt-18Q larvae did not. Furthermore, the authors examined the physiological defect underlying this disrupted larval locomotion in detail by recording spontaneous ongoing segmental nerve activity. NHtt-152QNLS larvae displayed uncoordinated activity between anterior and posterior segments. Moreover, anterior segments had shorter bursts and longer interburst intervals in NHtt-152QNLS larvae than in NHtt-18QNLS larvae, whereas posterior segments had longer bursts and shorter interburst intervals. These results suggest that the pathogenic protein disrupts neuron function without inducing cell death, and describe how this dysfunction leads to a locomotor defect. These results also suggest that sensory inputs are necessary for the coordination of anterior and posterior body parts during locomotion. From these analyses the authors show that examination of motor behaviors in the Drosophila larvae is a powerful new model to dissect non–cell-lethal mechanisms of mutant Htt toxicity.