Interleukin 1βreceptor and synaptic dysfunction in recurrent brain infection with Herpes simplex virus type-1

Several experimental evidence suggests a link between brain Herpes simplex virus type-1 infection and the occurrence of Alzheimer’s disease.However,the molecular mechanisms underlying this association are not completely understood.Among the molecular mediators of synaptic and cognitive dysfunction occurring after Herpes simplex virus type-1 infection and reactivation in the brain neuroinflammatory cytokines seem to occupy a central role.Here,we specifically reviewed literature reports dealing with the impact of neuroinflammation on synaptic dysfunction observed after recurrent Herpes simplex virus type-1 reactivation in the brain,highlighting the role of interleukins and,in particular,interleukin 1βas a possible target against Herpes simplex virus type-1-induced neuronal dysfunctions.

Resveratrol corrects aberrant splicing of RYR1 pre-mRNA and Ca2+ signal in myotonic dystrophy type 1 myotubes

Myotonic dystrophy type 1(DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1(RYR1), sarcoplasmatic/endoplasmatic Ca^2+-ATPase(SERCA) and α1 S subunit of voltage-gated Ca^2+ channels(Cav1.1) is related to Ca^2+ homeostasis and excitation-contraction coupling impairment. Though no pharmacological treatment for DM1 exists, aberrant splicing correction represents one major therapeutic target for this disease. Resveratrol(RES, 3,5,4′-trihydroxy-trans-stilbene) is a promising pharmacological tools for DM1 treatment for its ability to directly bind the DNA and RNA influencing gene expression and alternative splicing. Herein, we analyzed the therapeutic effects of RES in DM1 myotubes in a pilot study including cultured myotubes from two DM1 patients and two healthy controls. Our results indicated that RES treatment corrected the aberrant splicing of RYR1, and this event appeared associated with restoring of depolarization-induced Ca^2+ release from RYR1 dependent on the electro-mechanical coupling between RYR1 and Cav1.1. Interestingly, immunoblotting studies showed that RES treatment was associated with a reduction in the levels of CUGBP Elav-like family member 1, while RYR1, Cav1.1 and SERCA1 protein levels were unchanged. Finally, RES treatment did not induce any major changes either in the amount of ribonuclear foci or sequestration of muscleblind-like splicing regulator 1. Overall, the results of this pilot study would support RES as an attractive compound for future clinical trials in DM1. Ethical approval was obtained from the Ethical Committee of IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy(rs9879/14) on May 20, 2014.

Dual role of brain-derived extracellular vesicles in dementia-related neurodegenerative disorders: cargo of disease spreading signals and diagnostic-therapeutic molecules

Neurodegenerative disorders are one of the most common causes of disability and represent 6.3%of the global burden of disease.Among them,Alzheimer’s,Parkinson’s,and Huntington’s diseases cause cognitive decline,representing the most disabling symptom on both personal and social levels.The molecular mechanisms underlying the onset and progression of dementia are still poorly understood,and include secretory factors potentially affecting differentiated neurons,glial cells and neural stem cell niche.In the last decade,much attention has been devoted to exosomes as novel carriers of information exchanged among both neighbouring and distant cells.These vesicles can be generated and internalized by different brain cells including neurons,neural stem cells,astrocytes,and microglia,thereby affecting neural plasticity and cognitive functions in physiological and pathological conditions.Here,we review data on the roles of exosomes as carriers of bioactive molecules potentially involved in the pathogenesis of neurodegenerative disorders and detectable in biological fluids as biomarkers of dementia.We also discuss the experimental evidence of the therapeutic potential of stem cell-derived vesicles in experimental models of neurodegeneration-dependent cognitive decline.