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

View ORCID ProfileMI Oliveira da Silva, M Santejo, View ORCID ProfileIW Babcock, View ORCID ProfileA Magalhães, LS Minamide, View ORCID ProfileE Castillo, E Gerhardt, C Fahlbusch, View ORCID ProfileRA Swanson, View ORCID ProfileTF Outeiro, View ORCID ProfileJR Bamburg, View ORCID ProfileMA Liz
doi: https://doi.org/10.1101/2021.02.02.425931
MI Oliveira da Silva
1Neurodegeneration Team, Nerve Regeneration Group, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal, and i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
2ICBAS – Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
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M Santejo
1Neurodegeneration Team, Nerve Regeneration Group, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal, and i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
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IW Babcock
3Department of Biochemistry and Molecular Biology, Colorado State University, CO, USA
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A Magalhães
4Addiction Biology Group, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal, and i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
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LS Minamide
3Department of Biochemistry and Molecular Biology, Colorado State University, CO, USA
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E Castillo
5Department of Neurology, University of California, San Francisco, CA, USA
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E Gerhardt
6Department of Experimental Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany
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C Fahlbusch
6Department of Experimental Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany
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RA Swanson
5Department of Neurology, University of California, San Francisco, CA, USA
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TF Outeiro
6Department of Experimental Neurodegeneration, University Medical Center Göttingen, Göttingen, Germany
7Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Germany
8Max Planck Institute for Experimental Medicine, Göttingen, Germany
9Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK
10Scientific employee with a honorary contract at Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Göttingen, Germany
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JR Bamburg
3Department of Biochemistry and Molecular Biology, Colorado State University, CO, USA
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MA Liz
1Neurodegeneration Team, Nerve Regeneration Group, IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal, and i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal
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  • For correspondence: maliz@ibmc.up.pt
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Abstract

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.

Competing Interest Statement

The authors have declared no competing interest.

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Posted February 02, 2021.
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Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy
MI Oliveira da Silva, M Santejo, IW Babcock, A Magalhães, LS Minamide, E Castillo, E Gerhardt, C Fahlbusch, RA Swanson, TF Outeiro, JR Bamburg, MA Liz
bioRxiv 2021.02.02.425931; doi: https://doi.org/10.1101/2021.02.02.425931
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Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy
MI Oliveira da Silva, M Santejo, IW Babcock, A Magalhães, LS Minamide, E Castillo, E Gerhardt, C Fahlbusch, RA Swanson, TF Outeiro, JR Bamburg, MA Liz
bioRxiv 2021.02.02.425931; doi: https://doi.org/10.1101/2021.02.02.425931

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