Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin.
Huntington's disease is caused by an expanded CAG repeat in the gene encoding huntingtin (HTT), resulting in loss of striatal and cortical neurons. Given that the gene product is widely expressed, it remains unclear why neurons are selectively targeted. Here we show the relationship between synaptic and extrasynaptic activity, inclusion formation of mutant huntingtin protein (mtHtt) and neuronal survival. Synaptic N-methyl-D-aspartate-type glutamate receptor (NMDAR) activity induces mtHtt inclusions via a T complex-1 (TCP-1) ring complex (TRiC)-dependent mechanism, rendering neurons more resistant to mtHtt-mediated cell death. In contrast, stimulation of extrasynaptic NMDARs increases the vulnerability of mtHtt-containing neurons to cell death by impairing the neuroprotective cyclic AMP response element-binding protein (CREB)-peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) cascade and increasing the level of the small guanine nucleotide-binding protein Rhes, which is known to sumoylate and disaggregate mtHtt. Treatment of transgenic mice expressing a yeast artificial chromosome containing 128 CAG repeats (YAC128) with low-dose memantine blocks extrasynaptic (but not synaptic) NMDARs and ameliorates neuropathological and behavioral manifestations. By contrast, high-dose memantine, which blocks both extrasynaptic and synaptic NMDAR activity, decreases neuronal inclusions and worsens these outcomes. Our findings offer a rational therapeutic approach for protecting susceptible neurons in Huntington's disease.
Okamoto
Shu-ichi
S
Center for Neuroscience, Aging and Stem Cell Research, Burnham Institute for Medical Research, La Jolla, California, USA.
Pouladi
Mahmoud A
MA
Talantova
Maria
M
Yao
Dongdong
D
Xia
Peng
P
Ehrnhoefer
Dagmar E
DE
Zaidi
Rameez
R
Clemente
Arjay
A
Kaul
Marcus
M
Graham
Rona K
RK
Zhang
Dongxian
D
Vincent Chen
H-S
HS
Tong
Gary
G
Hayden
Michael R
MR
Lipton
Stuart A
SA
D000818:Animals; D016923:Cell Death / Q000502:physiology; D018244:Chromosomes, Artificial, Yeast; D000071058:Huntingtin Protein; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors
C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D015534:Trans-Activators; D014157:Transcription Factors; D008559:Memantine