Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy

Sara K. Custer, Jacob W. Astroski, Hong Xia Li, Elliot Androphy

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

We report that expression of the α-COP protein rescues disease phenotype in a severe mouse model of Spinal Muscular Atrophy (SMA). Lentiviral particles expressing α-COP were injected directly into the testes of genetically pure mouse strain of interest resulting in infection of the spermatagonial stem cells. α-COP was stably expressed in brain, skeletal muscle, and spinal cord without altering SMN protein levels. SMA mice transgenic for α-COP live significantly longer than their non-transgenic littermates, and showed increased body mass and normal muscle morphology at postnatal day 15. We previously reported that binding between SMN and α-COP is required for restoration of neurite outgrowth in cells lacking SMN, and we report similar finding here. Lentiviral-mediated transgenic expression of SMN where the dilysine domain in exon 2b was mutated was not able to rescue the SMA phenotype despite robust expression of the mutant SMN protein in brain, muscle and spinal cord. These results demonstrate that α-COP is a validated modifier of SMA disease phenotype in a mammalian, vertebrate model and is a potential target for development of future SMN-independent therapeutic interventions.

Original languageEnglish (US)
JournalBiochemical and Biophysical Research Communications
DOIs
StatePublished - Jan 1 2019

Fingerprint

Coatomer Protein
Spinal Muscular Atrophy
Muscle
Phenotype
lysyllysine
Brain
Spinal Cord
Proteins
Stem cells
Muscles
Restoration
Exons
Muscular Diseases
Mutant Proteins
Transgenic Mice
Vertebrates
Testis
Skeletal Muscle
Stem Cells
Infection

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy. / Custer, Sara K.; Astroski, Jacob W.; Li, Hong Xia; Androphy, Elliot.

In: Biochemical and Biophysical Research Communications, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "We report that expression of the α-COP protein rescues disease phenotype in a severe mouse model of Spinal Muscular Atrophy (SMA). Lentiviral particles expressing α-COP were injected directly into the testes of genetically pure mouse strain of interest resulting in infection of the spermatagonial stem cells. α-COP was stably expressed in brain, skeletal muscle, and spinal cord without altering SMN protein levels. SMA mice transgenic for α-COP live significantly longer than their non-transgenic littermates, and showed increased body mass and normal muscle morphology at postnatal day 15. We previously reported that binding between SMN and α-COP is required for restoration of neurite outgrowth in cells lacking SMN, and we report similar finding here. Lentiviral-mediated transgenic expression of SMN where the dilysine domain in exon 2b was mutated was not able to rescue the SMA phenotype despite robust expression of the mutant SMN protein in brain, muscle and spinal cord. These results demonstrate that α-COP is a validated modifier of SMA disease phenotype in a mammalian, vertebrate model and is a potential target for development of future SMN-independent therapeutic interventions.",
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