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Mol Neurobiol. 2018 May;55(5):4009-4029. doi: 10.1007/s12035-017-0589-0. Epub 2017 Jun 1.

Cytoskeleton-Associated Risk Modifiers Involved in Early and Rapid Progression of Sporadic Creutzfeldt-Jakob Disease.

Author information

1
Department of Neurology, Clinical Dementia Center, and DZNE, Georg-August University, University Medical Center Goettingen (UMG), Robert-Koch-Str. 40, 37075, Goettingen, Germany. sz_awaan@yahoo.com.
2
Department of Neurology, Clinical Dementia Center, and DZNE, Georg-August University, University Medical Center Goettingen (UMG), Robert-Koch-Str. 40, 37075, Goettingen, Germany.
3
Department of Zoology, University of the Punjab, Lahore, Pakistan.
4
Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Hospitalet de Llobregat, Spain.
5
Network Center for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Institute Carlos III, Ministry of Health, Madrid, Spain.
6
Institut National de la Recherche Agronomique/Ecole Nationale Vétérinaire, Toulouse, France.

Abstract

A high priority in the prion field is to identify pre-symptomatic events and associated profile of molecular changes. In this study, we demonstrate the pre-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 wild-type 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 F-actin, 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.

KEYWORDS:

APP; Actin; CJD; Cerebellum; Cofilin; Cortex; LIMK; MM1; Microglia; Prion protein; Rock; SSH1; VV2

PMID:
28573459
DOI:
10.1007/s12035-017-0589-0

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