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Introduction: despite neurofilaments are mainly expressed in large caliber myelinated axons, recent evidence supports the existence of a specific synaptic pool, where neurofilament light chain (NfL) has been proposed to stabilize NMDAR at post-synaptic membrane through a direct interaction with the GluN1 subunit. Here, we assessed the expression and synaptic abundance of neurofilaments and their interaction with NMDAR in experimental α-synucleinopathy models. Methods: we used confocal imaging and biochemical approaches to confirm NMDAR-NfL interaction at synapses. Western blotting in purified fractions and Co-IP were then performed to assess synaptic neurofilaments expression and GluN1-NfL interaction in (i) α-synuclein pre-formed fibrils- (α-syn PFF) treated hippocampal neuronal cultures and (ii) mice intrastriatally injected with α-syn-PFF. Results: we identified the existence of a direct protein-protein interaction between NMDAR and NfL endogenously expressed in neurons. Our findings showed increased striatal GluN1-NfL interaction levels at early phases of α-syn PFF-treated mice compared to controls (NfL/GluN1 optical density: α-syn PFF 0.71 ± 0.04; controls 0.48 ± 0.03; t(9) = 4.67; p = 0.001). In agreement with this observation, we found that NfL levels are increased in striatal post-synaptic fractions of α-syn PFF-treated mice (normalized optical density: α-syn PFF 1.86 ± 0.14; controls 1.34 ± 0.13 t(18) = 2.70; p = 0.015). Conclusions: our results demonstrate alterations of striatal synaptic neurofilament pool in α-synucleinopathy models and open the way to further investigations evaluating a potential role of neurofilaments dysregulation in explaining glutamatergic synaptic dysfunction observed in α-synucleinopathies such as Parkinson’s disease.

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