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DTSTART;TZID=Europe/Rome:20220926T150000
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SUMMARY:Prof. Vincenzo A. Gennarino – “Neurological disease: it’s not just about genes anymore”
DESCRIPTION:IGB Webinar 26 Settembre 2022Vincenzo A. Gennarino, Ph.D.\nAssistant Professor, Departments of Genetics & Development\nPediatrics and Neurology\nColumbia University Medical Center\n701 W. 168th Street, 1402 HHSC\nNew York, NY 10032\nphone: 212-305-7863\nvag2138@cumc.columbia.edu ( mailto:vag2138@cumc.columbia.edu )\n \nPersonal Statement\nMy lab combines genetic, bioinformatic, and molecular biological approaches to understand human neurogenetic diseases. I’ve been accumulating the skills to do this work since my graduate training. During my doctoral work in the lab of Dr. Sandro Banfi, I became interested in how microRNAs (miRNAs) regulate eye genes, but at the time there was no good way to identify the full set of target genes for a given miRNA. Various bioinformatics methods have been developed, but each one revealed a different set of targets for a particular miRNA. I took a different approach: I hypothesized that the target genes of a given miRNA are likely to belong to the same miRNA gene network and biological pathway, and therefore to be co-expressed. This basic idea led me to develop HOCTAR (Gennarino, et al., Genome Research, 2009) and then the more refined CoMeTa (Gennarino, et al., Genome Research, 2012), whose prediction accuracy reaches close to 100%, as calculated by analysis of previously characterized human miRNAs. CoMeTa was the first tool to infer the biological pathways of each human miRNA and identify its target genes. HOCTAR led to the discovery of the function of miR-128 in controlling TFEB, the master regulator of lysosomal biogenesis (Science, 2009).\nFor my postdoctoral work, I wanted to apply my expertise in RNA biology towards understanding how protein homeostasis is regulated in the brain in health and disease, so I joined the laboratory of Dr. Huda Y. Zoghbi at Baylor College of Medicine (Houston, TX). Huda is renowned for her discoveries of the genetic basis of several neurodegenerative and developmental disorders. In my first line of investigation I focused on Rett syndrome, a severe developmental disability caused by mutations in the MECP2 gene. I capitalized on the tools I had developed during my doctoral work and discovered that MECP2 levels are regulated by the microRNA miR-483-5p during human fetal development (Gennarino, et al., Genes & Development, 2013).  I then discovered that NUDT21 post-transcriptionally regulates MeCP2 protein levels through alternative polyadenylation sites in the MECP2 3’UTR. Not only is this finding important in the context of Rett Syndrome pathogenesis, but it led to the identification of a previously uncharacterized genetic cause for neurodevelopmental disease: patients who have copy number variations spanning NUDT21 suffer from intellectual disability, autism spectrum disorder and developmental regression, all of which are features shared with Rett syndrome (Gennarino, et al., eLife, 2015).\nFor my second line of research, I studied Spinocerebellar ataxia type 1 (SCA1). SCA1 is caused by the gradual accumulation of glutamine-expanded ATAXIN1 (ATXN1), and I sought to understand how post-transcriptional modification of ATXN1 influences protein levels. I discovered that the RNA-binding protein (RBP) PUM1 negatively regulates ATAXIN1 and that a 50% reduction of PUM1 increases wild-type ATXN1 levels by 30%-40%, which is enough to cause cerebellar degeneration and ataxia. Moreover, this degeneration can be rescued by normalizing ATXN1 levels. These data identified PUM1 as a candidate gene for neurological disease in humans (Gennarino et al., Cell, 2015). I then identified 20 human patients who carry loss-of-function mutations in PUM1 that produce early- or late-onset neurological phenotypes (Gennarino, et al., Cell, 2018).\nSince becoming an assistant professor at Columbia, my lab has been pursuing deeper studies of PUM1 and PUM2, which turn out to regulate a number of proteins important in neurological function. We have identified a larger number of patients with PUM1 mutations, and we are collaborating with clinicians to identify patients with mutations in PUM1-interacting proteins, which are involved in other neurodegenerative and neurodevelopmental disorders.\n
URL:https://www.igb.cnr.it/index.php/events/prof-vincenzo-a-gennarino-neurological-disease-its-not-just-about-genes-anymore/
ORGANIZER;CN=Floriana Della Ragione:MAILTO:floriana.dellaragione@igb.cnr.it
CATEGORIES:External Seminars
LOCATION:IGB Virtual Room
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