Cognitive dysfunction and dementia are presently recognized as major complications in alpha-synucleinopathies, namely in Dementia with Lewy Bodies (DLB) and Parkinsons disease with dementia (PDD). In these disorders, alpha-Synuclein (aSyn) accumulation affects severely the hippocampus by inducing synaptic dysfunction which culminates in cognitive impairment. To characterize the mechanisms underlying aSyn-induced neuronal dysfunction we analysed the effect of overexpression or extracellular administration of aSyn on hippocampal neurons. We observed that aSyn 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 aSyn-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 aSyn on Lewy Body dementias.
bioRxiv Subject Collection: Neuroscience