Abstract
Huntington disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Disrupted cortico-striatal transmission is an early event that contributes to neuronal spine and synapse dysfunction primarily in striatal medium spiny neurons, the most vulnerable cell type in the disease, but also in neurons of other brain regions including the cortex. Although striatal and cortical neurons eventually degenerate, these synaptic and circuit changes may underlie some of the earliest motor, cognitive, and psychiatric symptoms. Moreover, synaptic dysfunction and spine loss are hypothesized to be therapeutically reversible before neuronal death occurs, and restoration of normal synaptic function may delay neurodegeneration. One of the earliest synaptic alterations to occur in HD mouse models is enhanced striatal extrasynaptic NMDA receptor expression and activity. This activity is mediated primarily through GluN2B subunit-containing receptors and is associated with increased activation of cell death pathways, inhibition of survival signaling, and greater susceptibility to excitotoxicity. Death-associated protein kinase 1 (DAPK1) is a pro-apoptotic kinase highly expressed in neurons during development. In the adult brain, DAPK1 becomes re-activated and recruited to extrasynaptic NMDAR complexes during neuronal death, where it phosphorylates GluN2B at S1303, amplifying toxic receptor function. Approaches to reduce DAPK1 activity have demonstrated benefit in animal models of stroke, Alzheimer’s disease, Parkinson’s disease, and chronic stress, indicating that DAPK1 may be a novel target for neuroprotection. Here, we demonstrate that dysregulation of DAPK1 occurs early in the YAC128 HD mouse model, and contributes to elevated extrasynaptic GluN2B S1303 phosphorylation. Inhibition of DAPK1 normalizes extrasynaptic GluN2B phosphorylation and surface expression, and completely prevents YAC128 striatal spine loss in cortico-striatal co-culture, thus validating DAPK1 as a potential target for synaptic protection in HD and warranting further development of DAPK1-targeted therapies for neurodegeneration.
Highlights
Huntington disease (HD) is a debilitating and fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene (Huntington’s Disease Collaborative Research Group, 1993)
Given the established role of extrasynaptic N-methyl D-aspartate receptor (NMDAR) (exNMDAR) excitotoxicity in HD, we sought to evaluate whether Death-associated protein kinase 1 (DAPK1) is dysregulated in YAC128 mice
When we evaluated Dapk1 mRNA levels, we found no differences between genotypes (Figure 1D), suggesting altered DAPK1 protein stability or turnover in YAC128 brains, as opposed to elevated transcription
Summary
Huntington disease (HD) is a debilitating and fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene (Huntington’s Disease Collaborative Research Group, 1993). Neuronal dysfunction and degeneration have been reported in other brain regions including the cortex (Rüb et al, 2016). Studies show that cognitive, behavioral, and brain connectivity abnormalities are present decades before clinical onset in premanifest mutation carriers and that by the time of overt motor disturbances, there is significant irreversible neuronal death in the striatum (Vonsattel et al, 1985; Schippling et al, 2009; Tabrizi et al, 2009, 2011; Orth et al, 2010; Waldvogel et al, 2015). Neuroprotective therapies must be administered early in the disease time course such that synaptic dysfunction can be corrected before cell death. Strategies aimed at restoring the normal function of surviving neurons at later disease stages may still offer additional benefit
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