title: Modulation of GluN3A expression in Huntington disease: a new n-methyl-D-aspartate receptor-based therapeutic approach?
abstract: Huntington disease (HD) is an inherited neurodegenerative disorder with no cure or effective palliative treatment. An ideal therapy would arrest pathogenesis at early stages before neuronal damage occurs. However, although the genetic mutation that causes HD is known, the molecular chain of events that leads from the mutation to disease is not well understood. Accumulating evidence suggests that synaptic dysregulation may be involved, and the earliest known deficit is hyperfunction of glutamate-type N-methyl-d-aspartate receptors (NMDARs) in the selectively vulnerable medium spiny neurons of the striatum. A previous study found that the mutant Htt protein interferes with downregulation of juvenile NMDAR subtypes that contain GluN3A subunits by sequestering the endocytic adaptor PACSIN1 and preventing their removal from the cell surface. Loss of PACSIN1 and consequent gain of GluN3A function reactivate a synapse pruning mechanism that is important during development but harmful when active at later stages. Suppressing the GluN3A reactivation corrected the NMDAR hyperfunction and prevented the full range of HD signs and symptoms in mouse models, encouraging efforts to develop GluN3A-selective antagonists and/or explore alternative therapeutic approaches to block GluN3A expression.
authors: Cellular Neurobiology and Neurophysiology Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors: John F
authors: JF
authors: Wesseling
authors: Cellular Neurobiology and Neurophysiology Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors: Isabel
authors: I
authors: Pérez-Otaño
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: C584082:GluN3A protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate