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

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.

• Authors: Saima Zafar, Neelam Younas, Nadeem Sheikh, Waqas Tahir, Mohsin Shafiq, Matthias Schmitz, Isidre Ferrer, Olivier Andréoletti, Inga Zerr
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 55 Issue 5 Pg. 4009-4029 (May 2018) ISSN: 1559-1182 [Electronic] United States
• PMID: 28573459 (Publication Type: Journal Article)

Chemical References

• Actins
• Aif1 protein, mouse
• Amyloid beta-Peptides
• Calcium-Binding Proteins
• Cofilin 1
• Microfilament Proteins
• PrPC Proteins
• RNA, Small Interfering
• LIMK1 protein, human
• Lim Kinases
• ROCK2 protein, human
• rho-Associated Kinases
• Calcineurin
• Phosphoprotein Phosphatases
• SSH1 protein, human

Topics

• Actins (metabolism)
• Aged
• Amyloid beta-Peptides (metabolism)
• Animals
• Calcineurin (metabolism)
• Calcium-Binding Proteins (metabolism)
• Cell Survival
• Cells, Cultured
• Cofilin 1 (metabolism)
• Creutzfeldt-Jakob Syndrome (pathology)
• Cytoskeleton (metabolism)
• Disease Progression
• Female
• Gene Silencing
• Humans
• Lim Kinases (metabolism)
• Male
• Mice, Transgenic
• Microfilament Proteins (metabolism)
• Microglia (metabolism)
• Middle Aged
• Neurons (metabolism)
• Phosphoprotein Phosphatases (metabolism)
• Phosphorylation
• PrPC Proteins (metabolism)
• Protein Binding
• RNA, Small Interfering (metabolism)
• Risk Factors
• rho-Associated Kinases (metabolism)