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, PrP interaction with cofilin-1 and phosphorylated form of cofilin (p-cofilin(Ser3)) was investigated in primary cultures of mouse cortex neurons (PCNs) of PrP wild-type and knockout mice (PrP). Short-interfering RNA downregulation of active form of cofilin-1 resulted in the redistribution/downregulation of PrP, 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.

Critical Roles of Dual-Specificity Phosphatases in Neuronal Proteostasis and Neurological Diseases

“…Recently, it was demonstrated that cofilin can associate with the cellular form of prion protein (PrP C ) in sporadic Creutzfeldt-Jakob disease subtypes and higher levels of SSH1 could be detected in disease samples. This study creditably underscores the cofilin-SSH1 interaction as a contributor of neurodegeneration [ 94 ]. Further, PTEN is a lipid and protein phosphatase that inhibits PI3/AKT signaling and inhibiting PTEN has neuroprotective effects in an AD mouse model, amyloid-β toxicity, a PD model, and lab models of spinal muscular atrophy [ 95 ].…”

Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

“…[ [259][260][261][262][263][264] Familial Abnormal F-actin dynamics in interphase cells affect endocytic recycling. [267,268] Lissencephaly-1/OMIM#607432 Lissencephaly-1 (LIS1)(P43034)/PAFAH1B1…”

“…It is interesting to note that alterations in neuronal cytoskeleton physiology can also be used to monitor disease progression since they can even be detected in pre-clinical stages of specific neurodegenerative diseases. This is the case with the MM1 and VV2 subtypes of sporadic Creutzfeldt-Jakob disease (CJD), where cytoskeleton assembly dysregulation mediated by alterations in cofilin-1 and its upstream regulators LIMK1, SSH1, Rock2, and APP has been described in both mice and humans [268]. Importantly, the finding of mechanistic relationships between cofilin-1 phosphorylation, its interaction with the prion protein PrP C , and alterations in activated microglia, as well as the accumulation of a dense form of F-actin, were found in frontal cortex and cerebellum samples from individuals at the pre-clinical stage, highlighting the potential for early diagnosis held by the analysis of cytoskeleton alterations in neurodegeneration.…”

SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer’s disease

“…Patient cohort processing, neuropathological examination and brain tissue collection for this study were all conducted as previously described [90,91]. The post-mortem interval was between 3 and 18 h. Both spAD and rpAD samples had AD pathologies with Braak stage ≥ V. The samples for AD subtypes were included without co-pathologies.…”