Suppression of Neurodegeneration and Increased Neurotransmission Caused by Expanded Full-Length Huntingtin Accumulating in the Cytoplasm

• DOI: 10.1016/j.neuron.2007.11.025
• Publication Date: 2008-01-11T16:03:15Z
• Authors: Eliana Romero; Guang-Ho Cha; Patrik Verstreken; Cindy V. Ly; Robert E. Hughes; Hugo J. Bellen; Juan Botas
• Keywords: Cytoplasm; Neuroscience(all); Green Fluorescent Proteins; HUMDISEASE; Nerve Tissue Proteins; Eye; Synaptic Transmission; MOLNEURO; Animals, Genetically Modified; 03 medical and health sciences; Animals; Humans; Huntingtin Protein; Neurotransmitter Agents; 0303 health sciences; Behavior, Animal; Nuclear Proteins; 3. Good health; Disease Models, Animal; Huntington Disease; Larva; Mutation; Nerve Degeneration; Microscopy, Electron, Scanning; Calcium; Drosophila

Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by expansion of a translated CAG repeat in the N terminus of the huntingtin (htt) protein. Here we describe the generation and characterization of a full-length HD Drosophila model to reveal a previously unknown disease mechanism that occurs early in the course of pathogenesis, before expanded htt is imported into the nucleus in detectable amounts. We find that expanded full-length htt (128Qhtt(FL)) leads to behavioral, neurodegenerative, and electrophysiological phenotypes. These phenotypes are caused by a Ca2+-dependent increase in neurotransmitter release efficiency in 128Qhtt(FL) animals. Partial loss of function in synaptic transmission (syntaxin, Snap, Rop) and voltage-gated Ca2+ channel genes suppresses both the electrophysiological and the neurodegenerative phenotypes. Thus, our data indicate that increased neurotransmission is at the root of neuronal degeneration caused by expanded full-length htt during early stages of pathogenesis.