Transcellular spreading of huntingtin aggregates in the Drosophila brain.
A key feature of many neurodegenerative diseases is the accumulation and subsequent aggregation of misfolded proteins. Recent studies have highlighted the transcellular propagation of protein aggregates in several major neurodegenerative diseases, although the precise mechanisms underlying this spreading and how it relates to disease pathology remain unclear. Here we use a polyglutamine-expanded form of human huntingtin (Htt) with a fluorescent tag to monitor the spreading of aggregates in the Drosophila brain in a model of Huntington's disease. Upon expression of this construct in a defined subset of neurons, we demonstrate that protein aggregates accumulate at synaptic terminals and progressively spread throughout the brain. These aggregates are internalized and accumulate within other neurons. We show that Htt aggregates cause non-cell-autonomous pathology, including loss of vulnerable neurons that can be prevented by inhibiting endocytosis in these neurons. Finally we show that the release of aggregates requires N-ethylmalemide-sensitive fusion protein 1, demonstrating that active release and uptake of Htt aggregates are important elements of spreading and disease progression.
Laboratory of Genetics, University of Wisconsin, Madison, WI 53706 ganetzky@wisc.edu babcock2@wisc.edu.
Daniel T
DT
Babcock
Laboratory of Genetics, University of Wisconsin, Madison, WI 53706 ganetzky@wisc.edu babcock2@wisc.edu.
Barry
B
Ganetzky
D000818:Animals; D001921:Brain / Q000502:physiology*; D004330:Drosophila / Q000502:physiology*; D029721:Drosophila Proteins; D000071058:Huntingtin Protein; D007150:Immunohistochemistry; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000503:physiopathology*; D010455:Peptides / Q000235:genetics; D066329:Protein Aggregates / Q000502:physiology*; D057900:Transcytosis / Q000502:physiology*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D029721:Drosophila Proteins; C542005:Htt protein, Drosophila; D000071058:Huntingtin Protein; D008869:Microtubule-Associated Proteins; D010455:Peptides; D066329:Protein Aggregates; C097188:polyglutamine
Huntington's disease; disease model; expanded triplet repeat; neurodegeneration; transmission