title: 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-152Q(NLS), NHtt-152Q), or nonpathogenic (NHtt-18Q(NLS), 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-152Q(NLS) larvae had altered dendrite morphology and larval locomotion, whereas NHtt-152Q, NHtt-18Q(NLS), 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-152Q(NLS) larvae displayed uncoordinated activity between anterior and posterior segments. Moreover, anterior segments had shorter bursts and longer interburst intervals in NHtt-152Q(NLS) larvae than in NHtt-18Q(NLS) 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.
authors.affiliation: Laboratory of Cellular Neurobiology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Cagri
authors.initials: C
authors.lastname: Yalgin
authors.forename: Saori
authors.initials: S
authors.lastname: Akimoto
authors.forename: Joanna
authors.initials: J
authors.lastname: Doumanis
authors.forename: Ruiko
authors.initials: R
authors.lastname: Sasajima
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Miyakawa
authors.forename: Adrian W
authors.initials: AW
authors.lastname: Moore
authors.forename: Takako
authors.initials: T
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003712:Dendrites / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004330:Drosophila; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D007814:Larva / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008124:Locomotion / Q000235:genetics*; D009410:Nerve Degeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine