title: Impaired alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and function by mutant huntingtin.
abstract: Emerging evidence from studies of Huntington disease (HD) pathophysiology suggests that huntingtin (htt) and its associated protein HAP1 participate in intracellular trafficking and synaptic function. However, it is largely unknown whether AMPA receptor trafficking, which is crucial for controlling the efficacy of synaptic excitation, is affected by the mutant huntingtin with polyglutamine expansion (polyQ-htt). In this study, we found that expressing polyQ-htt in neuronal cultures significantly decreased the amplitude and frequency of AMPAR-mediated miniature excitatory postsynaptic current (mEPSC), while expressing wild-type huntingtin (WT-htt) increased mEPSC. AMPAR-mediated synaptic transmission was also impaired in a transgenic mouse model of HD expressing polyQ-htt. The effect of polyQ-htt on mEPSC was mimicked by knockdown of HAP1 and occluded by the dominant negative HAP1. Moreover, we found that huntingtin affected mESPC via a mechanism depending on the kinesin motor protein, KIF5, which controls the transport of GluR2-containing AMPARs along microtubules in dendrites. The GluR2/KIF5/HAP1 complex was disrupted and dissociated from microtubules in the HD mouse model. Together, these data suggest that AMPAR trafficking and function is impaired by mutant huntingtin, presumably due to the interference of KIF5-mediated microtubule-based transport of AMPA receptors. The diminished strength of glutamatergic transmission could contribute to the deficits in movement control and cognitive processes in HD conditions.
authors.affiliation: Department of Physiology and Biophysics, State University of New York, at Buffalo, School of Medicine and Biomedical Sciences, Buffalo, New York 14214, USA.
authors.forename: Madhuchhanda
authors.initials: M
authors.lastname: Mandal
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.forename: Ping
authors.initials: P
authors.lastname: Zhong
authors.forename: Jia
authors.initials: J
authors.lastname: Cheng
authors.forename: Lara J
authors.initials: LJ
authors.lastname: Duffney
authors.forename: Wenhua
authors.initials: W
authors.lastname: Liu
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Yuen
authors.forename: Alison E
authors.initials: AE
authors.lastname: Twelvetrees
authors.forename: Shihua
authors.initials: S
authors.lastname: Li
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
authors.forename: Josef T
authors.initials: JT
authors.lastname: Kittler
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D055366:Synaptic Potentials; D009435:Synaptic Transmission
chemical_list: C490758:Hap1 protein, mouse; C490757:Hap1 protein, rat; C506812:Htt protein, mouse; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D018091:Receptors, AMPA; C097188:polyglutamine; C104722:glutamate receptor ionotropic, AMPA 2