DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease
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 vulne...
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| Format: | Article |
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2020.590569/full |
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| author | Mandi E. Schmidt Nicholas S. Caron Amirah E. Aly Fanny L. Lemarié Louisa Dal Cengio Yun Ko Nikola Lazic Lisa Anderson Betty Nguyen Lynn A. Raymond Michael R. Hayden |
| author_facet | Mandi E. Schmidt Nicholas S. Caron Amirah E. Aly Fanny L. Lemarié Louisa Dal Cengio Yun Ko Nikola Lazic Lisa Anderson Betty Nguyen Lynn A. Raymond Michael R. Hayden |
| author_sort | Mandi E. Schmidt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T06:51:49Z |
| format | Article |
| id | doaj.art-b4cb13fb61c5467bbd2761b7d6e1c14c |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-23T06:51:49Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-b4cb13fb61c5467bbd2761b7d6e1c14c2022-12-21T17:56:24ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022020-11-011410.3389/fncel.2020.590569590569DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington DiseaseMandi E. Schmidt0Nicholas S. Caron1Amirah E. Aly2Fanny L. Lemarié3Louisa Dal Cengio4Yun Ko5Nikola Lazic6Lisa Anderson7Betty Nguyen8Lynn A. Raymond9Michael R. Hayden10Centre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaCentre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaCentre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaCentre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaCentre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaCentre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaCentre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaCentre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaCentre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaDepartment of Psychiatry and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, CanadaCentre for Molecular Medicine and Therapeutics, BC Children’s Hospital Research Institute, University of British Columbia, Vancouver, BC, CanadaHuntington 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.https://www.frontiersin.org/articles/10.3389/fncel.2020.590569/fullDAPK1synapticGluN2BpS1303Huntington diseaseYAC128 |
| spellingShingle | Mandi E. Schmidt Nicholas S. Caron Amirah E. Aly Fanny L. Lemarié Louisa Dal Cengio Yun Ko Nikola Lazic Lisa Anderson Betty Nguyen Lynn A. Raymond Michael R. Hayden DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease Frontiers in Cellular Neuroscience DAPK1 synaptic GluN2B pS1303 Huntington disease YAC128 |
| title | DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease |
| title_full | DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease |
| title_fullStr | DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease |
| title_full_unstemmed | DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease |
| title_short | DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease |
| title_sort | dapk1 promotes extrasynaptic glun2b phosphorylation and striatal spine instability in the yac128 mouse model of huntington disease |
| topic | DAPK1 synaptic GluN2B pS1303 Huntington disease YAC128 |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2020.590569/full |
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