Zafar, SaimaYounas, NeelamSheikh, NadeemTahir, WaqasShafiq, MohsinSchmitz, MatthiasFerrer, Isidro (Ferrer Abizanda)Andréoletti, OlivierZerr, Inga2019-10-072019-10-082018-05-010893-7648https://hdl.handle.net/2445/141810A high priority in the prion field is to identify pre-symptomatic events and associated profile of molecular changes. Inthisstudy,wedemonstratethepre-symptomatic dysregulation of cytoskeleton assembly and its associated cofilin-1 pathway in strain and brain region-specific manners in MM1 and VV2 subtype-specific Creutzfeldt-Jakob disease at clinical and pre-clinical stage. At physiological level, PrPC interaction with cofilin-1 and phosphorylated form of cofilin (p-cofilin(Ser3)) was investigated in primary cultures of mouse cortex neurons (PCNs) of PrPC wildtype and knockout mice (PrP−/−). Short-interfering RNA downregulation of active form of cofilin-1 resulted in the redistribution/downregulation of PrPC, increase of activated form of microglia, accumulation of dense form of Factin, and upregulation of p-cofilin(Ser3). This upregulated p-cofilin(Ser3) showed redistribution of expression predominantly in the activated form of microglia in PCNs. At pathological level, cofilin-1 expression was significantly altered in cortex and cerebellum in both humans and mice at pre-clinical stage and at early symptomatic clinical stage of the disease. Further, to better understand the possible mechanism of dysregulation of cofilin-1, we also demonstrated alterations in upstream regulators; LIM kinase isoform 1 (LIMK1), slingshot phosphatase isoform 1 (SSH1), RhoA-associated kinase (Rock2), and amyloid precursor protein (APP) in sporadic Creutzfeldt-Jakob disease MM1 mice and in human MM1 and VV2 frontal cortex and cerebellum samples. In conclusion, our findings demonstrated for the first time a key pre-clinical response of cofilin-1 and the associated pathway in prion disease.21 p.application/pdfeng(c) Humana Press., 2018Malaltia de Creutzfeldt-JakobPatologiaCitosqueletMetabolismeDegeneració (Patologia)Creutzfeldt-Jakob diseasePathologyCytoskeletonMetabolismDegeneration (Pathology)info:eu-repo/semantics/article6894822019-10-07info:eu-repo/semantics/openAccess28573459