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2018-05-01

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/141810

Cytoskeleton-associated risk modifiers involved in early and rapid progression of sporadic Creutzfeldt-Jakob disease

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Recurs relacionat

https://doi.org/10.1007/s12035-017-0589-0

Resum

A 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.

Matèries

Malaltia de Creutzfeldt-Jakob, Patologia, Citosquelet, Metabolisme, Degeneració (Patologia)

Matèries (anglès)

Creutzfeldt-Jakob disease, Pathology, Cytoskeleton, Metabolism, Degeneration (Pathology)

Citació

Col·leccions

Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citació

ZAFAR, Saima, et al. Cytoskeleton-associated risk modifiers involved in early and rapid progression of sporadic Creutzfeldt-Jakob disease. Molecular Neurobiology. 2018. Vol. 55, num. 5, pags. 4009-4029. ISSN 0893-7648. [consulted: 18 of August of 2026]. Available at: https://hdl.handle.net/2445/141810

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