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1:30-1:50 PM:  Prof. Fabio Di Domenico: Department of Biochemical Sciences “A. Rossi-Fanelli” - Sapienza University of Rome

Title: “Protein O-GlcNAc modification in the central nervous system: from nutrient sensing to the development of Alzheimer disease signatures.”

Abstract: Protein O-GlcNAc modification is a dynamic non-canonical form of protein O-Glycosylation considered a rheostat of cellular reprogramming under differential metabolic conditions. Alterations of nutrient availability in the brain, as observed in Alzheimer Disease and in other neurodegenerative disorders, lead to aberrant O-GlcNAc levels and trigger the development of neuropathological signatures. We analyzed by proteomics approaches the total and protein-specific levels of O-GlcNacylation, the O-GlcNAc cycling and the development of AD signatures in mouse models of both AD-like dementia (DS mice) and metabolic disease (high fat diet mice). Data on DS mice supported the presence of altered hippocampal O-GlcNAc levels and their implications in the AD-related neurodegenerative process. Accordingly, metabolic defects observed in high fat diet (HFD) mice promoted the impairment of protein O-GlcNAcylation, eventually resulting in mitochondrial defects, reduced energy consumption and in the development of AD signatures. By testing the effects of the O-GlcNAcylation inducer Thiamet-G to rescue brain alterations and AD development, we demonstrated its beneficial effect on cognition associated with the recovery of O-GlcNAc levels of protein belonging to key functional pathways, such as, neuronal architecture, stress response mechanisms and energy production. Our studies clarified the molecular mechanisms by which reduced protein O-GlcNAcylation promote the progression of brain pathology, thus laying the foundations to understand the main processes linking metabolic defects and neurodegenerative processes

Bio: Fabio Di Domenico is Full professor of Biochemistry at Sapienza University of Rome. He obtained his PhD degree in Biochemistry in 2009. Before gaining his current position, he performed his research under the supervision of Prof. Butterfield at ����vlog�ٷ����, where he has been involved in the application of redox proteomics to brain samples from Alzheimer patients. His research is currently focused in understanding the mechanisms that associates the alteration of protein homeostasis with the development of Alzheimer-like dementia. Collected data from his laboratory postulate that aberrant proteostasis, observed in both Alzheimer and Down syndrome patients, is strictly associated with the increase of oxidative damage as result of compromised antioxidant response and faulty protein degradative systems. Recently, his studies revealed that the reduction a nutrient sensing protein post translational modification, O-GlcNAc, might represents a key molecular link between metabolic defect and the development of Alzheimer Disease signatures.

1:50-2:10 PM: Prof. Eugenio Barone: Sapienza University of Rome

Title: “Insulin signaling alterations impair mitochondrial bioenergetics in the brain: identification of a novel molecular mechanism linking metabolic and neurodegenerative diseases.”

Abstract: Brain insulin signaling acts as a key regulator for gene expression and cellular metabolism, both events sustaining neuronal activity and synaptic plasticity mechanisms. Alterations of this pathway, known as brain insulin resistance, are associated with an increased risk of developing age-related cognitive decline and neurodegeneration. Studies from our group and in collaboration with Dr. Butterfield's group uncovered the role of the enzyme biliverdin reductase A (BVRA) that, beyond its activity in the degradation pathway of heme, is a novel regulator of the insulin signaling. BVRA is a direct target of the insulin receptor (IR), similar to the insulin receptor substrate-1 (IRS1). IR phosphorylates BVRA on specific Tyr residues and activates BVRA to function as a Ser/Thr/Tyr kinase. Moreover, downstream from IRS1, BVRA works as a scaffold protein favoring: the translocation of GLUT4-containing vesicles to the plasma membrane (to increase glucose uptake in response to insulin), the AKT-mediated inhibition of GSK3β (that promotes cell survival) and the AMPK-mediated inhibition of MTOR (that is involved in autophagy). Moreover, we recently discovered that BVRA regulates mitochondrial bioenergetics in response to insulin, thus supporting cell metabolism. Ground-breaking findings from our group revealed that oxidative stress-induced impairment of BVRA is a key event driving insulin resistance development either in the brain or in peripheral tissues. Conversely, rescuing BVRA activity reduces oxidative stress levels and ameliorate brain insulin signa