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

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.

• Authors: Sara K Custer, Jacob W Astroski, Hong Xia Li, Elliot J Androphy
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 514 Issue 2 Pg. 530-537 (06 25 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 31060774 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• Coatomer Protein
• Smn1 protein, mouse
• Survival of Motor Neuron 1 Protein

Topics

• Amino Acid Sequence
• Animals
• Brain (metabolism, pathology)
• Coatomer Protein (genetics, metabolism)
• Disease Models, Animal
• Exons
• Female
• Gene Expression Regulation
• Genetic Vectors (chemistry, metabolism)
• Humans
• Lentivirus (genetics, metabolism)
• Male
• Mice
• Mice, Transgenic
• Motor Neurons (metabolism, pathology)
• Muscle, Skeletal (metabolism, pathology)
• Muscular Atrophy, Spinal (genetics, mortality, pathology, therapy)
• Mutation
• Phenotype
• Protein Binding
• Signal Transduction
• Spinal Cord (metabolism, pathology)
• Survival Analysis
• Survival of Motor Neuron 1 Protein (genetics, metabolism)