Spinal muscular atrophy (SMA) is a motor neuron disease for which no effective treatment is currently available. SMA is caused by reduced levels of the evolutionarily conserved and ubiquitously expressed survival of motor neuron (SMN) protein. SMN together with several other core proteins forms the macromolecular SMN complex, which functions in the assembly of ribonucleoproteins (RNPs). While SMN is believed to assemble a variety of RNPs, to date its only well-characterized function is in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), critical components of the eukaryotic mRNA splicing machinery. Disruption of an SMN-dependent RNA splicing pathway has not yet been able to explain the underlying disease mechanisms in SMA, highlighting the significance of identifying additional pathways controlled by SMN. Our preliminary work identifies the assembly of the U7 snRNP - a RNP factor required for 3'-end processing of replication dependent histone mRNAs - as SMN-dependent in vivo. Disruption of this pathway due to SMN deficiency causes deregulation of histone synthesis with potentially detrimental effects on downstream cellular processes. This research project aims to build on these findings to identify the critical RNA and protein determinants of SMN-mediated U7 snRNP biogenesis, as well as to determine whether altered histone synthesis caused by U7 dysfunction contributes to cellular phenotypes caused by SMN deficiency, including motor neuron survival. Taken together, this project aims to characterize an SMN-dependent RNA pathway that is disrupted is SMA and may have deleterious cellular consequences with important implications in etiology of the disease. ! !

Public Health Relevance

Spinal muscular atrophy (SMA), a childhood neurodegenerative disease for which no effective treatment is currently available, is caused by a deficiency in the survival motor neuron (SMN) protein. To identify targets for effective SMA therapeutics, it is essential to characterize the fundamental biological pathways controlled by SMN. This project aims to characterize a novel SMN-dependent pathway that is disrupted in the disease in an effort to reveal novel disease mechanisms, which may provide new avenues for SMA therapeutic targeting.

Agency
National Institute of Health (NIH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS079002-03
Application #
8660102
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nuckolls, Glen H
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10032
Li, Darrick K; Tisdale, Sarah; Lotti, Francesco et al. (2014) SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease. Semin Cell Dev Biol 32:22-9
Li, Darrick K; Tisdale, Sarah; Espinoza-Derout, Jorge et al. (2013) A cell system for phenotypic screening of modifiers of SMN2 gene expression and function. PLoS One 8:e71965