Enhanced sensitivity of striatal neurons to axonal transport defects induced by mutant huntingtin.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease linked to a polyQ (polyglutamine) expansion in the huntingtin protein. Although general brain atrophy is found in HD patients, the striatum is the most severely affected region. Loss or mutant forms of huntingtin were reported to disrupt fast axonal transport in Drosophila, squid, and mice. However, previous work did not resolve whether mutant huntingtin affects global axonal transport or only a subset of cargoes, nor did it resolve whether striatal neurons are preferentially sensitive to huntingtin-mediated defects. We used amyloid precursor protein (APP)-yellow fluorescent protein and brain-derived neurotrophic factor (BDNF)-mCherry fusion proteins as markers for fast axonal transport when huntingtin is altered. We found that movement of APP and BDNF is impaired in striatal and hippocampal, but not cortical, neurons from presymptomatic homozygous mutant mice carrying 150Q huntingtin knock-in mutations. In addition, loss of huntingtin disrupts APP axonal transport, whereas overexpression of wild-type, but not mutant, huntingtin enhances APP transport in all three types of neurons tested. These data suggest that a loss of wild-type huntingtin function in fast axonal transport plays important roles in the development of cell-type-specific defects in HD.
Her
Lu-Shiun
LS
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Goldstein
Lawrence S B
LS
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D000071058:Huntingtin Protein; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins