# The COPA vesicle protein and pathogenesis of spinal muscular atrophy

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $386,415

## Abstract

ABSTRACT
The pathogenesis of motor neuron and muscle dysfunction in spinal muscular atrophy (SMA), a leading genetic
cause of infant mortality, is still unresolved. SMA results from low levels of the Survival Motor Neuron SMN
protein. The rationale underlying these experiments is our discovery that the SMN protein binds to and moves
in neurons together with the CopA protein, the largest constituent of the heptameric COPI coatomer complex.
The objective of this proposal is to determine the molecular mechanisms by which reduced SMN interaction
with COPI complex and loss of COPI activities leads to neurodegeneration. Golgi-derived COPI vesicles are
necessary for post-translational processing and transport of proteins and other cargoes between Golgi
apparatus and endoplasmic reticulum and secretory pathway. Golgi alterations have been observed in SMA,
amyotrophic lateral sclerosis, Alzheimer’s disease, and other neurodegenerative disorders. Our data
demonstrate that pathologically low levels of SMN alter the morphology and functionality of the Golgi
apparatus. The overall premise of this proposal is that the COPI complex is necessary for processing and
trafficking of cargoes essential for normal motor neuron maintenance. We have also shown that specific
mRNAs are found in association with COPI. One class of cargo emphasized in this grant is mRNA selected for
axonal transport. We propose genetic, biochemical, proteomic and transgenic approaches to define the
properties and activities of the COPI complex and its interactions with SMN and other potential binding
partners. We will create murine models to investigate the role of COPI in the neuron and perform correlative in
vivo studies of axonogenesis, RNA trafficking and pathologic biological outcomes. Because SMN physically
interacts with factors linked to other neurodegenerative diseases, thereby implicating commonality of causality,
these experiments should result in new insights into the aberrant processes occurring in these disorders.
Moreover, pharmacologic induction of the COPI pathway may represent a novel objective for treatment of SMA
and other neurodegenerative diseases.

## Key facts

- **NIH application ID:** 9924683
- **Project number:** 5R01NS082284-07
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** ELLIOT J. ANDROPHY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $386,415
- **Award type:** 5
- **Project period:** 2013-08-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924683

## Citation

> US National Institutes of Health, RePORTER application 9924683, The COPA vesicle protein and pathogenesis of spinal muscular atrophy (5R01NS082284-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9924683. Licensed CC0.

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