Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy
Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy
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.
Santejo M、Minamide LS、Fahlbusch C、Liz MA、Castillo E、Outeiro TF、Magalh?es A、Oliveira da Silva MI、Swanson RA、Bamburg JR、Babcock IW、Gerhardt E
Neurodegeneration Team, Nerve Regeneration Group, IBMC ¨C Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal, and i3S - Instituto de Investiga??o e Inova??o em Sa¨2de, Universidade do PortoDepartment of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Experimental Neurodegeneration, University Medical Center G?ttingenNeurodegeneration Team, Nerve Regeneration Group, IBMC ¨C Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal, and i3S - Instituto de Investiga??o e Inova??o em Sa¨2de, Universidade do PortoDepartment of Neurology, University of CaliforniaDepartment of Experimental Neurodegeneration, University Medical Center G?ttingen||Cluster of Excellence ?°Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells?± (MBExC), University of G?ttingen||Max Planck Institute for Experimental Medicine||Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University||Scientific employee with a honorary contract at Deutsches Zentrum f¨1r Neurodegenerative Erkrankungen (DZNE)Addiction Biology Group, IBMC ¨C Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal, and i3S - Instituto de Investiga??o e Inova??o em Sa¨2de, Universidade do PortoNeurodegeneration Team, Nerve Regeneration Group, IBMC ¨C Instituto de Biologia Molecular e Celular, Universidade do Porto, Portugal, and i3S - Instituto de Investiga??o e Inova??o em Sa¨2de, Universidade do Porto||ICBAS ¨C Instituto de Ci¨oncias Biom¨|dicas Abel Salazar, Universidade do PortoDepartment of Neurology, University of CaliforniaDepartment of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Biochemistry and Molecular Biology, Colorado State UniversityDepartment of Experimental Neurodegeneration, University Medical Center G?ttingen
神经病学、精神病学基础医学分子生物学
Lewy Body dementiasalpha-Synucleinneurodegenerationactincofilin-1cofilin-actin rodssynaptic dysfunction
Santejo M,Minamide LS,Fahlbusch C,Liz MA,Castillo E,Outeiro TF,Magalh?es A,Oliveira da Silva MI,Swanson RA,Bamburg JR,Babcock IW,Gerhardt E.Cofilin pathology is a new player on α-synuclein-induced spine impairment in models of hippocampal synucleinopathy[EB/OL].(2025-03-28)[2025-05-29].https://www.biorxiv.org/content/10.1101/2021.02.02.425931.点此复制
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