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Restored Fyn Levels in Huntington's Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB
Lígia Fão1,2, Patrícia Coelho1, Ricardo J Rodrigues1,3
1Center for Neuroscience and Cell Biology (CNC), University of Coimbra (Pólo I), Rua Larga, 3004-504 Coimbra, Portugal.
Cells
|October 14, 2022
Summary
Reduced Fyn protein in Huntington's disease (HD) impairs N-methyl-D-aspartate receptors (NMDARs) at synapses, leading to excitotoxicity. Restoring Fyn kinase activity protects neurons by improving NMDAR function and activating survival pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- N-methyl-D-aspartate receptors (NMDARs) are crucial for synaptic function but can cause excitotoxicity when overactivated, as seen in Huntington's disease (HD).
- Altered NMDAR currents and distribution, particularly increased extrasynaptic GluN2B-containing NMDARs, are observed in HD striatal neurons.
- Fyn protein, a Src kinase family member, regulates NMDAR phosphorylation and localization, and its levels are reduced in HD models.
Purpose of the Study:
- To investigate the impact of reduced Fyn levels on postsynaptic density (PSD) NMDARs in Huntington's disease.
- To explore Fyn's role in NMDAR dysfunction, neuroprotection, and cell survival in YAC128 mouse striatal neurons.
- To determine if modulating Fyn kinase activity can restore NMDAR function and promote neuronal survival in HD.
Main Methods:
- Primary striatal neurons from YAC128 HD mouse model and wild-type littermates were used.
- Western blotting and immunoprecipitation were employed to assess protein levels and phosphorylation.
- Electrophysiological recordings were performed to analyze NMDAR currents.
- Expression of a constitutively active Src kinase family (SKF) was used to restore Fyn activity.
Main Results:
- Reduced synaptic Fyn levels in HD neurons correlated with decreased phosphorylation of synaptic GluN2B-NMDARs.
- HD neurons exhibited increased extrasynaptic NMDAR activity and reduced activation of the neuroprotective CREB pathway.
- Restoring SKF activity normalized NMDAR localization and phosphorylation at the PSD.
- Enhanced SKF activity promoted CREB activation and reduced caspase-3 activation, indicating reduced cell death.
Conclusions:
- Reduced Fyn protein in the PSD contributes to NMDAR dysfunction and excitotoxicity in Huntington's disease.
- Fyn kinase activity plays a critical role in modulating synaptic NMDAR function and activating neuroprotective pathways.
- Targeting Fyn tyrosine kinase activity presents a potential therapeutic strategy for Huntington's disease by enhancing neuronal survival.
