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Understanding and modulating synaptic dysfunction in Huntington disease Schmidt, Mandi Elizabeth

Abstract

Huntington disease (HD) is a devastating neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Early disrupted cortico-striatal (CS) transmission contributes to neuronal spine and synapse dysfunction primarily in striatal medium spiny neurons (MSNs), the most vulnerable cell type in HD, as well as in cortical neurons. Irreversible neurodegeneration of MSNs occurs with disease progression, leading to motor, cognitive, and psychiatric symptoms. However, synaptic dysfunction and spine loss are hypothesized to be therapeutically reversible before neuronal death occurs. One of the earliest alterations to occur in HD mouse models is enhanced striatal extrasynaptic (ex) N-methyl-D-aspartate receptor (NMDAR) expression and activity. This activity is mediated primarily through GluN2B subunit-containing receptors and is linked to 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. DAPK1 becomes re-activated and recruited to exNMDARs during ischemia where it phosphorylates GluN2B at S1303, amplifying receptor function. Approaches to reduce DAPK1 activity have demonstrated benefit in animal models of stroke, Alzheimer disease, Parkinson disease, and chronic stress, indicating that DAPK1 may be a novel target for neuroprotection. The overall hypothesis of this thesis was that aberrant DAPK1 activity contributes to exGluN2B dysfunction in HD, leading to early CS synaptic instability. An in vitro CS co-culture model was extensively optimized to allow rapid and robust detection of HD-like CS synaptic phenotypes, including MSN spine loss. Early dysregulation of DAPK1 was observed in the YAC128 HD mouse model, which was associated with elevated exGluN2B pS1303. Inhibition of DAPK1 normalized exGluN2B phosphorylation and surface expression, and completely prevented YAC128 MSN spine loss in CS co-culture. DAPK1 silencing restored nuclear CREB activation and partially rescued age-associated dendritic spine loss in vivo, thus validating DAPK1 as a target for synaptic protection in HD and warranting development of DAPK1-targeted therapies for neurodegeneration.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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