# RNA-Mediated Mechanisms of Motor System Dysfunction in Spinal Muscular Atrophy

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $408,886

## Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by
degeneration of motor neurons in the spinal cord and progressive atrophy of skeletal muscle. SMA is the most
frequent inherited cause of infant mortality and no treatment is currently available for the disease. SMA is
caused by a deficiency in the ubiquitously expressed survival motor neuron (SMN) protein due to homozygous
deletion or mutation of the SMN1 gene. Despite a clear genetic basis of the disease and progress in the
knowledge of SMN biology, the molecular mechanisms of SMA are poorly understood. SMN has a well-
established function in the biogenesis of small nuclear ribonucleoproteins (snRNPs) that are critical for RNA
splicing and 3' end formation of histone mRNAs. Moreover, it is becoming increasingly clear that SMN has
additional functions in RNA regulation that might also contribute to SMA. However, although SMN plays a
central role in post-transcriptional gene regulation, the contribution of specific SMN-dependent RNA pathways
to SMA pathology remains elusive. A major challenge in SMA research is to identify which SMN-dependent
RNA pathways and downstream genes among many potentially dysregulated events are directly relevant to
the disease phenotype. This is critically important to elucidate the molecular mechanisms of this devastating
disease and may also help to develop therapeutic approaches distinct from SMN upregulation. This project
aims to determine the direct contribution of three specific and well-established SMN-dependent RNA pathways
- U12 splicing, U7 snRNP biogenesis, and alternative splicing - to motor system dysfunction in a mouse model
of the disease that provides the best recapitulation of the human condition both genetically and phenotypically.
Our hypothesis is that specific defects in these pathways are causally linked to distinct functional abnormalities
of the SMA motor system. To address this hypothesis, we will investigate both the role of disruption of each of
these RNA pathways in SMA pathology and their requirement for normal motor system development using,
respectively, selective restoration (Aim 1) and inhibition (Aim 2) approaches in mouse models. These studies
will be combined with RNA profiling of select motor circuit neuron populations with the aim of identifying the
transcriptome alterations induced by SMN deficiency that are specifically associated with each RNA pathway
and their respective downstream gene targets that may directly contribute to the disease process, the
functional relevance of which will be tested in SMA mice (Aim 3). Collectively, this project is designed to
determine the RNA-dependent mechanisms of synaptic dysfunction and motor neuron death in SMA.

## Key facts

- **NIH application ID:** 10113678
- **Project number:** 5R01NS102451-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Livio Pellizzoni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $408,886
- **Award type:** 5
- **Project period:** 2017-06-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113678

## Citation

> US National Institutes of Health, RePORTER application 10113678, RNA-Mediated Mechanisms of Motor System Dysfunction in Spinal Muscular Atrophy (5R01NS102451-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10113678. Licensed CC0.

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