Sung Bae Lee, Joshua A. Bagley, Hye Young Lee, Lily Yeh Jan, and Yuh-Nung Jan1
Howard Hughes Medical Institute, Department of Physiology, Biochemistry, and Biophysics, University of California, San Francisco, CA 94143-0725
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.
disease model, genetic study
1To whom correspondence should be addressed.
Author contributions: S.B.L., L.Y.J., and Y.-N.J. designed research; S.B.L., J.A.B., and H.Y.L. performed research; S.B.L. contributed new reagents/analytic tools; S.B.L. and J.A.B. analyzed data; and S.B.L., L.Y.J., and Y.-N.J. wrote the paper.