Ricerc@Sapienza

The identification of the mechanisms predisposing to stroke may improve its preventive and therapeutic strategies in patients with essential hypertension. The role of macroautophagy/autophagy in the development of hypertension-related stroke needs to be clarified. We hypothesized that a defective autophagy may favor hypertension-related spontaneous stroke by promoting mitochondrial dysfunction. We studied autophagy in the stroke-prone spontaneously hypertensive (SHRSP) rat, which represents a clinically relevant model of stroke associated with high blood pressure.

Caloric restriction mimetics (CRMs) are emerging as potential therapeutic agents for the treatment of cardiovascular diseases. CRMs include natural and synthetic compounds able to inhibit protein acetyltransferases, to interfere with acetyl coenzyme A biosynthesis or to activate (de)acetyltransferase proteins. These modifications mimic the effects of caloric restriction, which is associated with the activation of autophagy.

Down syndrome (DS) is the most common genomic disorder characterized by the increased incidence of developing early Alzheimer’s disease (AD). In DS, the triplication of genes on chromosome 21 is intimately associated with the increase of AD pathological hallmarks and with the development of brain redox imbalance and aberrant proteostasis.

Cachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle atrophy in cancer patients, yet poorly described in human cachexia. We herein investigated mitochondrial morphology, autophagy and apoptosis in the skeletal muscle of patients with gastrointestinal cancer-associated cachexia (CC), as compared with a weight-stable cancer group (WSC).

Signalling of the epithelial splicing variant of fibroblast growth factor receptor 2 (FGFR2b) triggers both differentiation and autophagy, while the aberrant expression of the mesenchymal FGFR2c isoform in epithelial cells induces impaired differentiation, inhibition of autophagy as well as the induction of the epithelial-mesenchymal transition (EMT).

Autophagy agonists have been proposed to slow down neurodegeneration. Spermidine, a polyamine that acts as an autophagy agonist, is currently under clinical trial for the treatment of age-related memory decline. How Spermidine and other autophagy agonists regulate memory and synaptic plasticity is under investigation.

Background: Down syndrome (DS) individuals, by the age of 40s, are at increased risk to develop Alzheimer-like dementia, with deposition in brain of senile plaques and neurofibrillary tangles. Our laboratory recently demonstrated the disturbance of PI3K/AKT/mTOR axis in DS brain, prior and after the development of Alzheimer Disease (AD). The aberrant modulation of the mTOR signalling in DS and AD age-related cognitive decline affects crucial neuronal pathways, including insulin signaling and autophagy, involved in pathology onset and progression.

Introduction: Autophagy is one of the most conserved clearance systems through which eukaryotes manage to handle dysfunctional and excess organelles and macromolecules. This catabolic process has not only a role in the maintenance of basal turnover of cellular components, but it is also essential in cells adaptation to stress conditions. In the last decades, defects in autophagic machinery have been identified as a feature in neurodegenerative diseases.

Biliverdin reductase-A (BVR-A) impairment is associated with increased accumulation of oxidatively-damaged proteins along with the impairment of autophagy in the brain during neurodegenerative disorders. Reduced autophagy inhibits the clearance of misfolded proteins, which then form neurotoxic aggregates promoting neuronal death. The aim of our study was to clarify the role for BVR-A in the regulation of the mTOR/autophagy axis by evaluating age-associated changes (2, 6 and 11 months) in cerebral cortex samples collected from BVR-A knock-out (BVR-A−/−) and wild-type (WT) mice.

Protein O-GlcNAcylation is a nutrient-related post-translational modification that, since its discovery some 30 years ago, has been associated with the development of neurodegenerative diseases. As reported in Alzheimer’s disease (AD), flaws in the cerebral glucose uptake translate into reduced hexosamine biosynthetic pathway flux and subsequently lead to aberrant protein O-GlcNAcylation. Notably, the reduction of O-GlcNAcylated proteins involves also tau and APP, thus promoting their aberrant phosphorylation in AD brain and the onset of AD pathological markers.