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Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity in the ∆7 SMA Mouse.

McGovern VL, Massoni-Laporte A, Wang X, Le TT, Le HT, Beattie CE, Rich MM, Burghes AH - PLoS ONE (2015)

Bottom Line: The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded.High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice.Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.

ABSTRACT
Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of SMN2. The SMN2 copy number inversely correlates with phenotypic severity and is a modifier of disease outcome. The SMN2 gene essentially differs from SMN1 by a single nucleotide in exon 7 that modulates the incorporation of exon 7 into the final SMN transcript. The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded. However the SMN2 gene does produce some full-length SMN and the SMN2 copy number along with how much full-length SMN the SMN2 gene makes correlates with severity of the SMA phenotype. However there are a number of discordant SMA siblings that have identical haplotypes and SMN2 copy number yet one has a milder form of SMA. It has been suggested that Plastin3 (PLS3) acts as a sex specific phenotypic modifier where increased expression of PLS3 modifies the SMA phenotype in females. To test the effect of PLS3 overexpression we have over expressed full-length PLS3 in SMA mice. To ensure no disruption of functionality or post-translational processing of PLS3 we did not place a tag on the protein. PLS3 protein was expressed under the Prion promoter as we have shown previously that SMN expression under this promoter can rescue SMA mice. High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice. Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons.

No MeSH data available.


Related in: MedlinePlus

Weight of each PrP:PLS3 transgenic line in the presence and absence of mouse Smn.Mice were weighted every day until weaning at 21 days of age. Each of the three PrP:PLS3 transgenic lines (PLS-14+/-, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 22, average max. weight 3.9g), (PLS-39+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 20, average max. weight 3.5g), (PLS-46+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 32 average max. weight 3.7g) weigh slightly less than Δ7 SMA mice (SMN2+/+; Smn-/-; Δ7SMN+/+, n = 11, average max. weight 4.0g). There is no statistical difference in weight between SMA mice (Smn-/-) with or without the transgene.
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pone.0132364.g006: Weight of each PrP:PLS3 transgenic line in the presence and absence of mouse Smn.Mice were weighted every day until weaning at 21 days of age. Each of the three PrP:PLS3 transgenic lines (PLS-14+/-, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 22, average max. weight 3.9g), (PLS-39+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 20, average max. weight 3.5g), (PLS-46+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 32 average max. weight 3.7g) weigh slightly less than Δ7 SMA mice (SMN2+/+; Smn-/-; Δ7SMN+/+, n = 11, average max. weight 4.0g). There is no statistical difference in weight between SMA mice (Smn-/-) with or without the transgene.

Mentions: We measured the weight of PrP:PLS3 mice to determine if overexpression of PLS3 in neurons increased the weight of Δ7 SMA the mouse. We found that the weight is not increased in three PrP:PLS3 transgenic lines in the Δ7 SMA mouse (Fig 6). The weight of each PrP:PLS3 transgenic line in the presence and absence of mouse Smn was measured daily until weaning at 21 days of age. The three PrP:PLS3 transgenic lines (PLS-14+/-, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 22, average max. weight 3.9g), (PLS39+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 20, average max. weight 3.5g), (PLS-46+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 32 average max. weight 3.7g) weigh slightly less than Δ7 SMA mice (SMN2+/+; Smn-/-; Δ7SMN+/+, n = 11, average max. weight 4.0g). There is no statistical difference in weight between Δ7 SMA mice or any of the transgenic PrP:PLS3 expressing lines as determined by the CompareGrowthCurve function found in the R-Package (Statmod).


Plastin 3 Expression Does Not Modify Spinal Muscular Atrophy Severity in the ∆7 SMA Mouse.

McGovern VL, Massoni-Laporte A, Wang X, Le TT, Le HT, Beattie CE, Rich MM, Burghes AH - PLoS ONE (2015)

Weight of each PrP:PLS3 transgenic line in the presence and absence of mouse Smn.Mice were weighted every day until weaning at 21 days of age. Each of the three PrP:PLS3 transgenic lines (PLS-14+/-, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 22, average max. weight 3.9g), (PLS-39+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 20, average max. weight 3.5g), (PLS-46+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 32 average max. weight 3.7g) weigh slightly less than Δ7 SMA mice (SMN2+/+; Smn-/-; Δ7SMN+/+, n = 11, average max. weight 4.0g). There is no statistical difference in weight between SMA mice (Smn-/-) with or without the transgene.
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pone.0132364.g006: Weight of each PrP:PLS3 transgenic line in the presence and absence of mouse Smn.Mice were weighted every day until weaning at 21 days of age. Each of the three PrP:PLS3 transgenic lines (PLS-14+/-, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 22, average max. weight 3.9g), (PLS-39+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 20, average max. weight 3.5g), (PLS-46+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 32 average max. weight 3.7g) weigh slightly less than Δ7 SMA mice (SMN2+/+; Smn-/-; Δ7SMN+/+, n = 11, average max. weight 4.0g). There is no statistical difference in weight between SMA mice (Smn-/-) with or without the transgene.
Mentions: We measured the weight of PrP:PLS3 mice to determine if overexpression of PLS3 in neurons increased the weight of Δ7 SMA the mouse. We found that the weight is not increased in three PrP:PLS3 transgenic lines in the Δ7 SMA mouse (Fig 6). The weight of each PrP:PLS3 transgenic line in the presence and absence of mouse Smn was measured daily until weaning at 21 days of age. The three PrP:PLS3 transgenic lines (PLS-14+/-, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 22, average max. weight 3.9g), (PLS39+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 20, average max. weight 3.5g), (PLS-46+/+, SMN2+/+; Smn-/-; Δ7SMN+/+, n = 32 average max. weight 3.7g) weigh slightly less than Δ7 SMA mice (SMN2+/+; Smn-/-; Δ7SMN+/+, n = 11, average max. weight 4.0g). There is no statistical difference in weight between Δ7 SMA mice or any of the transgenic PrP:PLS3 expressing lines as determined by the CompareGrowthCurve function found in the R-Package (Statmod).

Bottom Line: The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded.High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice.Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.

ABSTRACT
Spinal muscular atrophy is caused by loss of the SMN1 gene and retention of SMN2. The SMN2 copy number inversely correlates with phenotypic severity and is a modifier of disease outcome. The SMN2 gene essentially differs from SMN1 by a single nucleotide in exon 7 that modulates the incorporation of exon 7 into the final SMN transcript. The majority of the SMN2 transcripts lack exon 7 and this leads to a SMN protein that does not effectively oligomerize and is rapidly degraded. However the SMN2 gene does produce some full-length SMN and the SMN2 copy number along with how much full-length SMN the SMN2 gene makes correlates with severity of the SMA phenotype. However there are a number of discordant SMA siblings that have identical haplotypes and SMN2 copy number yet one has a milder form of SMA. It has been suggested that Plastin3 (PLS3) acts as a sex specific phenotypic modifier where increased expression of PLS3 modifies the SMA phenotype in females. To test the effect of PLS3 overexpression we have over expressed full-length PLS3 in SMA mice. To ensure no disruption of functionality or post-translational processing of PLS3 we did not place a tag on the protein. PLS3 protein was expressed under the Prion promoter as we have shown previously that SMN expression under this promoter can rescue SMA mice. High levels of PLS3 mRNA were expressed in motor neurons along with an increased level of PLS3 protein in total spinal cord, yet there was no significant beneficial effect on the phenotype of SMA mice. Specifically, neither survival nor the fundamental electrophysiological aspects of the neuromuscular junction were improved upon overexpression of PLS3 in neurons.

No MeSH data available.


Related in: MedlinePlus