The COPA vesicle protein and pathogenesis of spinal muscular atrophy

Project: Research project

Project Details


We discovered that the SMN protein binds to alpha-COP, the largest constituent of the heptameric COPI
vesicle. The hypothesis to be investigated in this project is that pathogenesis of SMA results from inability of
this cargo transport complex to sustain the functional integrity of motor neurons. We explore the role of the
SMN protein's interaction with alpha-COP in neurite development and maintenance. Importantly, we observed
that over-expression of alpha-COP restores neurite development in SMN depleted NSC34 cells. New data
reveal that low levels of SMN alter the functionality of endoplasmic reticulum-Golgi trafficking, suggesting a
previously unrecognized effect on this protein processing pathway. We recently reported that the alpha-COP
complex incorporates ~800 specific RNAs from the total transcriptome of differentiated NSC-34 cells. A high
fraction of these mRNAs contain in their 3' untranslated regions a G-quadruplex motif, which has been
assigned a role in neurite localization. Our goal is to identify the mRNAs that depend on SMN for association
with the COPI complex, enabling studies of the roles of alpha-COP and SMN in the trafficking of these RNAs
into the axon and characterization of their requirement for neuronal development. To examine the biological
physiologic significance of the interaction of SMN with alpha-COP and subsequent mechanistic studies, we
generated novel transgenic mice with reduced levels of alpha-COP protein, with the prediction this will result in
motor unit dysfunction. We also have created a transgenic strain that over-expresses tagged human alpha-
COP. These mice will be crossed with SMA model mice with low levels of SMN to test the hypothesis that
increased levels of alpha-COP and COPI vesicles promote SMN dependent cargo delivery to the axon and
restore motor skills and increase lifespan. These experimental mouse models will be important resources to
study the mechanism of neurodegeneration and the transport of proteins and specific RNAs to and within the
axon. Pharmacologic induction of the COPI pathway may represent a novel means to treat SMA.
Effective start/end date8/15/135/31/18


  • National Institutes of Health: $55,689.00
  • National Institutes of Health: $337,451.00
  • National Institutes of Health: $340,848.00
  • National Institutes of Health: $340,871.00
  • National Institutes of Health: $341,250.00


  • Medicine(all)
  • Neuroscience(all)

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