Research Faculty

P&S Room 5-421
Mail Code # 62
630 W 168th St.
New York, NY 10032

Phone: 212-305-3046
Fax: 212-342-0276
Education and Training
1992 B.Sc. University of Rome La Sapienza, Italy
1995 Ph.D. University of Rome Tor Vergata, Italy

Integrated Program
MD-PhD Program
Moto Neuron Center
Neurobiology & Behavior
Stem Cell Consortium

Internal collaborations: George Mentis, Brian McCabe, Neil Shneider, Umrao Monani, Jose Silva, Chris Henderson

Outside collaborations: Arthur Burghes (OSU), Christine Beattie (OSU) Charlotte Sumner (JHU), Chris Lorson (MU)

Intl Collaborations
International collaborations: Jernej Ule (UCL)
Livio Pellizzoni, Ph.D
Assistant Professor of Pathology & Cell Biology
Research Summary

Ribonucleoprotein complexes in post-transcriptional gene regulation and motor neuron disease

Motor control is essential for complex human behaviors such as swallowing, breathing and locomotion. The coordinated activity of motor neurons and their networked neurons and muscle fibers is critical for motor system function and disruption of this network underlies fatal human disorders such as spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS)—the two most common motor neuron diseases of infancy and adulthood, respectively. Importantly, increasing evidence links these diseases to mutations in ubiquitously expressed genes implicated in RNA processing and post-transcriptional gene regulation. However, knowledge of the normal functions of these genes is still limited and the disease mechanisms remain poorly understood. Moreover, a prominent unsolved conundrum common to other neurodegenerative disorders is how disruption of ubiquitously expressed proteins can cause dysfunction or death of specific subsets of neurons. Our work focuses on addressing these fundamental questions using SMA as a paradigm.

SMA is an inherited disorder characterized by degeneration of motor neurons in the spinal cord and atrophy of skeletal muscle, and represents the leading genetic cause of death in infancy. SMA patients are homozygous for deletions or mutations in the survival motor neuron (SMN1) gene, but retain at least one copy of the hypomorphic SMN2 gene. SMN2 produces low levels of full-length SMN protein that cannot compensate for the loss of SMN1, resulting in SMA. Thus, SMA is caused by a ubiquitous deficiency in SMN where remaining levels appear sufficient for function and survival of most cell types, but not of motor neurons. Our previous work helped establish SMN’s essential role in RNA processing and a link between RNA dysregulation and SMA pathology. SMN is part of a macromolecular complex that functions in the biogenesis of small nuclear ribonucleoproteins (snRNPs) - which are essential components of the splicing machinery that catalyze intron removal from mRNA precursors in the nucleus - as well as other RNPs. The SMN complex functions as a molecular chaperone to increase the efficiency and specificity of RNP assembly, and to provide an opportunity for RNA-protein interactions to be regulated in vivo.

Research in my laboratory takes advantage of the unique position of SMN at the nexus between RNA regulation and motor neuron biology to advance our understanding of the mechanisms controlling the biogenesis and function of RNPs in post-transcriptional gene regulation and how disruption in these processes contributes to neurodegenerative disease. The underlying logic of our approach is that studies of SMN’s basic functions in RNA regulation will provide the key to understanding disease mechanisms and, conversely, that analysis of motor neuron pathology will uncover new fundamental aspects of SMN biology. To reach this multidisciplinary goal, we employ cell and animal models as well as a wide range of biochemical, molecular and cell biological methodologies. High-throughput screening approaches are also used to identify chemical and genetic modifiers of SMN biology and disease pathways. On one hand, these efforts are designed to increase our knowledge of fundamental mechanisms that control RNA processing and their involvement in motor neuron survival and function. On the other, they aim to deconstruct disease mechanisms and identify potential therapeutic approaches.

Selected Publications

1. S. Tisdale, F. Lotti, L. Saieva, J.P. Van Meerbeke, T.O. Crawford, C.J. Sumner, G.Z. Mentis and L. Pellizzoni. SMN is essential for the biogenesis of U7 small nuclear ribonucleoprotein and 3’-end formation of histone mRNAs. Cell Rep., 2013, 5, 1187-1195.

2. F. Lotti, W.L. Imlach, L. Saieva, E.S. Beck, L.T. Hao, D.K. Li, W. Jiao, G.Z.M. Mentis, C.E. Beattie, B.D. McCabe and L. Pellizzoni. A SMN-dependent U12 splicing event essential for motor circuit function. Cell, 2012, 151, 440-454.

3. W.L. Imlach, E.S. Beck, B.J. Choi, F. Lotti, L. Pellizzoni and B.D. McCabe. SMN is required for sensory-motor circuit function in Drosophila. Cell, 2012, 151, 427-439.

4. M. Ruggiu, V.L. McGovern, F. Lotti, L. Saieva, D.K. Li, S. Kariya, U.R. Monani, A.H.M. Burghes and L. Pellizzoni. A role for SMN exon 7 splicing in the selective vulnerability of motor neurons in Spinal Muscular Atrophy. Mol. Cell. Biol., 2012, 32, 126-138.

5. E. Workman, L. Saieva, T.L. Carrel, T.O. Crawford, D. Liu, C. Lutz, C.E. Beattie, L. Pellizzoni and A.H. Burghes. A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice. Hum. Mol. Genet., 2009, 18, 2215-2229.

6. F. Gabanella, M.E.R. Butchbach, L. Saieva, C. Carissimi, A.H. Burghes and L. Pellizzoni. Ribonucleoprotein assembly defects correlate with spinal muscular atrophy severity and preferentially affect a subset of spliceosomal snRNPs. PLoS ONE, 2007, 2, e921.

7. L. Pellizzoni. Chaperoning ribonucleoprotein biogenesis in health and disease. EMBO Rep., 2007, 8, 340-345

8. F. Gabanella, C. Carissimi, A. Usiello and L. Pellizzoni. The activity of the Spinal Muscular Atrophy protein is regulated during development and cellular differentiation. Hum. Mol. Genet., 2005, 14, 3629-3642.

9. L. Pellizzoni, J. Yong and G. Dreyfuss. Essential role for the SMN complex in the specificity of snRNP assembly. Science, 2002, 298, 1775-1779.

Honors and Awards

Laurea Summa Cum Laude, University of Rome La Sapienza

Doctoral Degree in Biotechnology Summa Cum Laude, University of Rome Tor Vergata

EMBO Young Investigator Award

Telethon Career Award
Committees , Council, and Professional Society Memberships

American Society for Biochemistry and Molecular Biology
RNA Society
New York Academy of Science
Society for Neuroscience
American Society for Cell Biology
American Society for Microbiology

Post-transcriptional gene regulation, RNA processing, RNA splicing, RNA-protein complexes, snRNP, SMN, neurodegeneration, SMA, ALS

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