α-Synuclein triggers cofilin pathology and dendritic spine impairment via a PrPC-CCR5 dependent pathway

• Published in: Cell death & disease Vol. 15; no. 4; p. 264
• Main Authors: Oliveira da Silva, Marina I., Santejo, Miguel, Babcock, Isaac W., Magalhães, Ana, Minamide, Laurie S., Won, Seok-Joon, Castillo, Erika, Gerhardt, Ellen, Fahlbusch, Christiane, Swanson, Raymond A., Outeiro, Tiago F., Taipa, Ricardo, Ruff, Michael, Bamburg, James R., Liz, Márcia A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-04-2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 13/51; 13/95; 14; 14/19; 42/109; 631/80; 631/80/82; 64/60; Actin; Animal models; Antibodies; Biochemistry; Biomedical and Life Sciences; CC chemokine receptors; Cell Biology; Cell Culture; Chemokine receptors; Cofilin; Cognitive ability; Dementia disorders; Dendritic spines; Fibrils; Hippocampus; Immunology; Lewy bodies; Life Sciences; Molecular modelling; Pathology; Prion protein; Rods; Synuclein; Therapeutic targets
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06630-9

Cognitive dysfunction and dementia are critical symptoms of Lewy Body dementias (LBD). Specifically, alpha-synuclein (αSyn) accumulation in the hippocampus leading to synaptic dysfunction is linked to cognitive deficits in LBD. Here, we investigated the pathological impact of αSyn on hippocampal neurons. We report that either αSyn overexpression or αSyn pre-formed fibrils (PFFs) treatment triggers the formation of cofilin-actin rods, synapse disruptors, in cultured hippocampal neurons and in the hippocampus of synucleinopathy mouse models and of LBD patients. In vivo, cofilin pathology is present concomitantly with synaptic impairment and cognitive dysfunction. Rods generation prompted by αSyn involves the co-action of the cellular prion protein (PrP
C
) and the chemokine receptor 5 (CCR5). Importantly, we show that CCR5 inhibition, with a clinically relevant peptide antagonist, reverts dendritic spine impairment promoted by αSyn. Collectively, we detail the cellular and molecular mechanism through which αSyn disrupts hippocampal synaptic structure and we identify CCR5 as a novel therapeutic target to prevent synaptic impairment and cognitive dysfunction in LBD.