Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm.
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.
Romero
Eliana
E
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Cha
Guang-Ho
GH
Verstreken
Patrik
P
Ly
Cindy V
CV
Hughes
Robert E
RE
Bellen
Hugo J
HJ
Botas
Juan
J
D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D002118:Calcium / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism*; D004195:Disease Models, Animal; D004330:Drosophila; D005123:Eye / Q000473:pathology / Q000648:ultrastructure; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease; D007814:Larva; D008855:Microscopy, Electron, Scanning / Q000379:methods; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D009687:Nuclear Proteins; D049452:Green Fluorescent Proteins; D002118:Calcium