Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy

Oliveira da Silva, M. I.; Santejo, M.; Babcock, I. W.; Magalhaes, A.; Minamide, L. S.; Castillo, E.; Gerhardt, E.; Fahlbusch, C.; Swanson, R. A.; Outeiro, T. F.; Bamburg, J. R.; Liz, M. A.

doi:10.1101/2021.02.02.425931

bioRxiv · 10.1101/2021.02.02.425931

Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy

Oliveira da Silva, M. I.·Santejo, M.·Babcock, I. W.·Magalhaes, A.·Minamide, L. S.·Castillo, E.·Gerhardt, E.·Fahlbusch, C.·Swanson, R. A.·Outeiro, T. F.·Bamburg, J. R.·Liz, M. A.

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Abstract

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

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Oliveira da Silva, M. I., Santejo, M., Babcock, I. W., Magalhaes, A., Minamide, L. S., Castillo, E., Gerhardt, E., Fahlbusch, C., Swanson, R. A., Outeiro, T. F., Bamburg, J. R., Liz, M. A.. 2021-02-02. Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy. https://doi.org/10.1101/2021.02.02.425931

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