title: Pathogenic polyglutamine proteins cause dendrite defects associated with specific actin cytoskeletal alterations in Drosophila.
abstract: Whereas the neurodegeneration associated with various polyglutamine (polyQ) diseases has prompted extensive studies of polyQ-induced cell death, the neuronal loss that typically appears during late stages of the diseases may not account for the preceding movement and mental disorders. The cellular basis for polyQ-induced neuronal dysfunction preceding neuronal cell death remains largely unknown. Here we report defective dendrite morphogenesis within a specific subset of neurons due to polyQ toxicity that can be dissociated from caspase-dependent cell death. Expressing pathogenic spinocerebellar ataxia type 1 (SCA1) or type 3 (SCA3) proteins in Drosophila larval dendritic arborization neurons caused neuronal type-specific dendrite phenotypes primarily affecting terminal branches. We further show that expression of pathogenic polyQ proteins in adult flies after the formation of neuronal dendrites also greatly reduced dendritic complexity. These defects are associated with disruption of dendritic F-actin structures that can be partially mitigated by increasing Rac-PAK signaling. Together, these findings suggest that specific actin cytoskeletal alterations that alter dendrite morphology and function may contribute to the pathogenesis of at least a subset of polyQ disorders, including SCA3 and SCA1.
authors.affiliation: Department of Physiology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143-0725, USA.
authors.forename: Sung Bae
authors.initials: SB
authors.lastname: Lee
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Bagley
authors.forename: Hye Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Lily Yeh
authors.initials: LY
authors.lastname: Jan
authors.forename: Yuh-Nung
authors.initials: YN
authors.lastname: Jan
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000067528:Ataxins; D003599:Cytoskeleton / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D004330:Drosophila / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D007814:Larva / Q000378:metabolism / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D059008:Time-Lapse Imaging
chemical_list: D000199:Actins; D000067528:Ataxins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D049452:Green Fluorescent Proteins; C097188:polyglutamine