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Vincenzo Alessandro Gennarino, PhD


Address: Hammer Health Sciences 701 West 168th Street, 14th Floor- Room 1402 New York NY 10032
Phone: 212-305-4011
Fax: 212-923-2090
E-mail:

vag2138@cumc.columbia.edu

Education and Training:
Master's degree in Biological Science, summa cun laude 2009, A. Monroy University of Palermo
PhD in Medical Genetics 2005, Telethon Institute of Genetics and Medicine (TIGEM), Second University
Affiliations:
bullet  Genetics and Development Department
bullet  Pediatrics Department
bullet  Neurology Department
Training Activities:
Research Summary:
(800 words, max)
Accumulating evidence indicates that the brain is very sensitive to the levels of various proteins, with too much or too little being equally disruptive. Among neurodevelopmental diseases, we have the example of Rett Syndrome (too little MeCP2) and MeCP2 duplication syndrome (too much MeCP2). Among neurodegenerative diseases we have the “proteinopathies,” such as Parkinson’s disease and Huntington’s disease, which involve problems with protein folding and clearance; in most cases there is a mutation that alters the function of the disease-causing protein and causes it to accumulate over time in neurons, but too much wild-type protein is also problematic: duplication of the amyloid precursor protein (APP) locus causes early-onset Alzheimer’s disease, and duplications of alpha-synuclein (SNCA) cause familial Parkinson’s disease. These observations led us to ask whether more modest elevations of protein levels also cause disease. In particular, could aberrant RNA processing and post-transcriptional regulation of specific proteins alter their steady-state levels sufficiently to cause many neurodegenerative and neuropsychiatric disorders?

The short answer is yes (see publications). The coordinated activities of microRNA (miRNA) and RNA-binding proteins (RBPs) regulate mRNA turnover, localization and translation, and orchestrate hundreds of circuits that are responsible for proper cognitive function. In our lab we use a combination of high-throughput genomic approaches and bioinformatic analysis along with molecular genetics, biochemistry, cell biology, and animal behavior studies to understand RNA homeostasis and control of protein dosage in the brain. The goal of our research is to unveil new regulatory mechanisms of specific disease-driving genes and to identify new neurological disease genes, with the ultimate goal of developing novel therapeutic strategies.
Current Research:
We currently have two main projects. The first stems from our discovery that mutations in Pumilio1 (PUM1), an RNA-binding protein, cause a neurodegenerative disease reminiscent of spinocerebellar ataxia type 1 (SCA1). SCA1 is caused by the gradual accumulation of polyglutamine-expanded ATXN1. We discovered that PUM1 negatively regulates ATXN1 levels and is also necessary for normal neurodevelopment. In mice, Pum1 deficiency increases WT Atxn1 mRNA and protein levels by about 40%. Removing a copy of Atxn1 in these mice reduced SCA1-like pathology by normalizing WT Atxn1 levels (Gennarino et al., Cell). This led us to propose that PUM1 mutations in humans would also cause disease, and we have begun identifying patients with mutations or chromosomal deletions in PUM1 to investigate its role in the human brain.

The second project builds on our discovery that the CFIm protein complex regulates MeCP2 protein levels. MECP2, the gene involved in Rett syndrome, is peculiar for having a very long (~8.5 kb) 3’UTR that contains two prominent poly-adenylation (p(A)) sites: a proximal p(A) and a distal p(A), resulting in short and long messenger mRNA isoforms, respectively. Through alternative polyadenylation (APA), a gene can give rise to multiple mRNA isoforms of their 3’UTRs, allowing them to be acted upon by post-transcriptional regulatory factors such miRNAs and RBPs. In vitro and structural studies have shown that CFIm binds pre-mRNA as a heterotetrameric complex composed of a CFIm25 dimer and two paralogs, CFIm59 and CFIm68, which regulates 3’UTR isoforms by APA. Despite several in vitro attempts to explain the role of the CFIm protein complex in APA, the mechanism remains elusive and its in vivo role is unknown. We identified eleven individuals with neuropsychiatric disease who have copy number variations (CNVs) spanning NUDT21 (CFIm25), which regulates MeCP2 protein levels by APA sites in the MECP2 3’UTR. These individuals suffer from autism spectrum disorder and notable developmental regression, very similar to Rett Syndrome. We thus discovered that NUDT21 duplication is a cause of neuropsychiatric disease along the autism spectrum (Gennarino et al., eLife). We are expanding our studies to identify the role of the CFIm complex in other human neurological diseases.


PostDoctoral and Research Technician positions are available starting January 15, 2018.

*To apply please send your CV and Cover Letter to: vag2138@columbia.edu

Publications:
(6 max)
1. Gennarino VA*, Alcott CA*, Chen CA, Chaudhury A, Rosenfeld JA, Parikh S, Wheless JW, Roeder ER, Horovitz DDG, Roney EK, Smith JL, Cheung SW, Li W, Nailson JR, Schaaf CP, Zoghbi HY. (*Contributed equally): (2015) “NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation.” .  eLife, Aug 27  4: 10.7554/eLife.10782

2. Gennarino VA, Singh RK, White JJ, De Maio A, Han K, Kim JY, Jafar-Nejad P, di Ronza A, Kang H, Sayegh LS, Cooper TA, Orr HT, Sillitoe RV and Zoghbi HY. : (2012) “Pumilio1 Haploinsufficiency Leads to SCA1-like Neurodegeneration by Increasing Wild-Type Ataxin1 Levels.”(This paper was highlighted in an ALZ forum press release).  Cell, March 12  160(6): 1087-98

3. Han K*, Gennarino VA*, Lee Y, Pang K, Hashimoto-Torii K, Choufani S, Raju CS, Oldham MC, Weksberg R, Rakic P, Liu Z, and Zoghbi HY. (*Contributed equally) : (2013) “Human-specific regulation of MeCP2 levels in fetal brains by microRNA miR-483-5p.” (This paper was selected for the journal cover).  Genes & Development, Mar 1  27(5): 485-90

4. Gennarino VA, D’angelo G, Dharmalingam G, Fernandez S, Russolillo G, Sanges R, Mutarelli M, Belcastro V, Ballabio A, Verde P, Sardiello M, Banfi S.: (2012) “Identification of microRNA-regulated gene networks by expression analysis of target genes.”.  Genome Research, June  22(6): 1163-72. Epub 2012 Feb 24.

5. Gennarino VA†, Sardiello M, Mutarelli M, Dharmalingam G, Maselli V, Lago G and Banfi S.(†Corresponding author).: (2011) “HOCTAR database: a unique resource for microRNA target prediction.” .  Gene, July 1  480(1-2): 51-8

6. Gennarino VA, Sardiello M, Avellino R, Meola N, Maselli V, Anand S, Cutillo L, Ballabio A and Banfi S. : (2009) “MicroRNA target prediction by expression analysis of host genes.” .  Genome Research, March  19(3): 481-90. Epub 2008 Dec 16.

URL for lab page:
 

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