Oliveira da Silva MI , Santejo M, Babcock IW, Magalhães A, Minamide LS, Castillo E, Gerhardt E, Fahlbusch C, Swanson RA, Outeiro TF, Bamburg JR, Liz MA
Cognitive dysfunction and dementia are presently recognized as major complications in α-synucleinopathies, namely in Dementia with Lewy Bodies (DLB) and Parkinson’s disease with dementia (PDD). In these disorders, α-Synuclein (αSyn) accumulation affects severely the hippocampus by inducing synaptic dysfunction which culminates in cognitive impairment. To characterize the mechanisms underlying αSyn-induced neuronal dysfunction we analysed the effect of overexpression or extracellular administration of αSyn on hippocampal neurons. We observed that αSyn induces the dysregulation of the actin-binding protein cofilin and its assembly into rod structures in a mechanism mediated by the cellular prion protein (PrPC). Moreover, we unraveled cofilin pathology as mediator of αSyn-induced dendritic spine impairment in hippocampal neurons. Importantly, in a synucleinopathy mouse model with cognitive impairment we validated cofilin dysregulation and synaptic dysfunction at the same age when cognitive deficits were observed. Our data supports cofilin as a novel player on hippocampal synaptic dysfunction triggered by αSyn on Lewy Body dementias.