title: Suppressing aberrant GluN3A expression rescues synaptic and behavioral impairments in Huntington's disease models.
abstract: Huntington's disease is caused by an expanded polyglutamine repeat in the huntingtin protein (HTT), but the pathophysiological sequence of events that trigger synaptic failure and neuronal loss are not fully understood. Alterations in N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDARs) have been implicated. Yet, it remains unclear how the HTT mutation affects NMDAR function, and direct evidence for a causative role is missing. Here we show that mutant HTT redirects an intracellular store of juvenile NMDARs containing GluN3A subunits to the surface of striatal neurons by sequestering and disrupting the subcellular localization of the endocytic adaptor PACSIN1, which is specific for GluN3A. Overexpressing GluN3A in wild-type mouse striatum mimicked the synapse loss observed in Huntington's disease mouse models, whereas genetic deletion of GluN3A prevented synapse degeneration, ameliorated motor and cognitive decline and reduced striatal atrophy and neuronal loss in the YAC128 Huntington's disease mouse model. Furthermore, GluN3A deletion corrected the abnormally enhanced NMDAR currents, which have been linked to cell death in Huntington's disease and other neurodegenerative conditions. Our findings reveal an early pathogenic role of GluN3A dysregulation in Huntington's disease and suggest that therapies targeting GluN3A or pathogenic HTT-PACSIN1 interactions might prevent or delay disease progression.
authors.affiliation: Cellular Neurobiology and Neurophysiology Laboratories, Centro de Investigación Médica Aplicada y Universidad de Navarra, Pamplona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Marco
authors.forename: Albert
authors.initials: A
authors.lastname: Giralt
authors.forename: Milos M
authors.initials: MM
authors.lastname: Petrovic
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
authors.forename: Rebeca
authors.initials: R
authors.lastname: Martínez-Turrillas
authors.forename: José
authors.initials: J
authors.lastname: Martínez-Hernández
authors.forename: Linda S
authors.initials: LS
authors.lastname: Kaltenbach
authors.forename: Jesús
authors.initials: J
authors.lastname: Torres-Peraza
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nakanishi
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Lipton
authors.forename: Donald C
authors.initials: DC
authors.lastname: Lo
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: John F
authors.initials: JF
authors.lastname: Wesseling
authors.forename: Isabel
authors.initials: I
authors.lastname: Pérez-Otaño
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001522:Behavior, Animal; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003598:Cytoskeletal Proteins; D004195:Disease Models, Animal; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D017072:Neostriatum / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020836:Protein Structure, Quaternary; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D045442:Rotarod Performance Test; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C548929:GRIN3A protein, human; C584082:GluN3A protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C114726:Pacsin1 protein, mouse; C117738:Pacsin1 protein, rat; D010750:Phosphoproteins; D016194:Receptors, N-Methyl-D-Aspartate