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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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Marco S,Giralt A,Petrovic MM,Pouladi MA,Martínez-Turrillas R,Martínez-Hernández J,Kaltenbach LS,Torres-Peraza J,Graham RK,Watanabe M,Luján R,Nakanishi N,Lipton SA,Lo DC,Hayden MR,Alberch J,Wesseling JF,Pérez-Otaño I

doi

10.1038/nm.3246

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

1030-8

issue

8

eissn

1078-8956

issn

1546-170X

pii

nm.3246

journal_volume

19

pub_type

杂志文章

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