Disruption of Axonal Transport by Loss of Huntingtin or Expression of Pathogenic PolyQ Proteins in Drosophila

Shermali Gunawardena, Lu-Shiun Her, Richard G. Brusch, Robert A. Laymon, Ingrid R. Niesman, Beth Gordesky-Gold, Louis Sintasath, Nancy M. Bonini and Lawrence S.B. Goldstein

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093 USA
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093 USA
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104 USA

We tested whether proteins implicated in Huntington's and other polyglutamine (polyQ) expansion diseases can cause axonal transport defects. Reduction of Drosophila huntingtin and expression of proteins containing pathogenic polyQ repeats disrupt axonal transport. Pathogenic polyQ proteins accumulate in axonal and nuclear inclusions, titrate soluble motor proteins, and cause neuronal apoptosis and organismal death. Expression of a cytoplasmic polyQ repeat protein causes adult retinal degeneration, axonal blockages in larval neurons, and larval lethality, but not neuronal apoptosis or nuclear inclusions. A nuclear polyQ repeat protein induces neuronal apoptosis and larval lethality but no axonal blockages. We suggest that pathogenic polyQ proteins cause neuronal dysfunction and organismal death by two non-mutually exclusive mechanisms. One mechanism requires nuclear accumulation and induces apoptosis; the other interferes with axonal transport. Thus, disruption of axonal transport by pathogenic polyQ proteins could contribute to early neuropathology in Huntington's and other polyQ expansion diseases.