Abstract
Heterozygosity for mutations (N88S and P90L) in the N-glycosylation site of seipin/BSCL2 is associated with the autosomal dominant motor neuron diseases, spastic paraplegia 17 and distal hereditary motor neuropathy type V, referred to as 'seipinopathies'. Previous in vitro studies have shown that seipinopathy-linked mutations result in accumulation of unfolded proteins in the endoplasmic reticulum (ER), leading to the unfolded protein response and cell death, suggesting that seipinopathies is closely associated with ER stress. To further understand the molecular pathogenesis of seipinopathies, we generated a transgenic (tg) mouse line expressing the human N88S seipin mutant with the murine Thy-1 promoter to permit analyses of in vivo phenotypic changes. The N88S seipin tg mice develop a progressive spastic motor deficit, reactive gliosis in the spinal cord and neurogenic muscular atrophy, recapitulating the symptomatic and pathological phenotype in patients of seipinopathy. We also found that expression of mutant seipin in mice upregulated the ER stress marker, immunoglobulin-heavy-chain-binding protein, protein disulfide isomerase and X-box binding protein 1, but was not linked to significant neuronal loss in affected tissue, thereby indicating that ER stress is sufficient, while neuronal death is not necessary, for the development of motor phenotypes of seipinopathies. Our findings in the mutant seipin tg mouse provide clues to understand the relationship with ER stress and neurodegeneration, and the seipin tg mouse is a valid tool for the development of novel therapeutic strategies against ER stress-related diseases.
| Original language | English |
|---|---|
| Article number | ddr304 |
| Pages (from-to) | 3831-3840 |
| Number of pages | 10 |
| Journal | Human Molecular Genetics |
| Volume | 20 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - 2011 Oct |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
Cite this
N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress. / Yagi, Takuya; Ito, Daisuke; Nihei, Yoshihiro; Ishihara, Tadayuki; Suzuki, Norihiro.
In: Human Molecular Genetics, Vol. 20, No. 19, ddr304, 10.2011, p. 3831-3840.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress
AU - Yagi, Takuya
AU - Ito, Daisuke
AU - Nihei, Yoshihiro
AU - Ishihara, Tadayuki
AU - Suzuki, Norihiro
PY - 2011/10
Y1 - 2011/10
N2 - Heterozygosity for mutations (N88S and P90L) in the N-glycosylation site of seipin/BSCL2 is associated with the autosomal dominant motor neuron diseases, spastic paraplegia 17 and distal hereditary motor neuropathy type V, referred to as 'seipinopathies'. Previous in vitro studies have shown that seipinopathy-linked mutations result in accumulation of unfolded proteins in the endoplasmic reticulum (ER), leading to the unfolded protein response and cell death, suggesting that seipinopathies is closely associated with ER stress. To further understand the molecular pathogenesis of seipinopathies, we generated a transgenic (tg) mouse line expressing the human N88S seipin mutant with the murine Thy-1 promoter to permit analyses of in vivo phenotypic changes. The N88S seipin tg mice develop a progressive spastic motor deficit, reactive gliosis in the spinal cord and neurogenic muscular atrophy, recapitulating the symptomatic and pathological phenotype in patients of seipinopathy. We also found that expression of mutant seipin in mice upregulated the ER stress marker, immunoglobulin-heavy-chain-binding protein, protein disulfide isomerase and X-box binding protein 1, but was not linked to significant neuronal loss in affected tissue, thereby indicating that ER stress is sufficient, while neuronal death is not necessary, for the development of motor phenotypes of seipinopathies. Our findings in the mutant seipin tg mouse provide clues to understand the relationship with ER stress and neurodegeneration, and the seipin tg mouse is a valid tool for the development of novel therapeutic strategies against ER stress-related diseases.
AB - Heterozygosity for mutations (N88S and P90L) in the N-glycosylation site of seipin/BSCL2 is associated with the autosomal dominant motor neuron diseases, spastic paraplegia 17 and distal hereditary motor neuropathy type V, referred to as 'seipinopathies'. Previous in vitro studies have shown that seipinopathy-linked mutations result in accumulation of unfolded proteins in the endoplasmic reticulum (ER), leading to the unfolded protein response and cell death, suggesting that seipinopathies is closely associated with ER stress. To further understand the molecular pathogenesis of seipinopathies, we generated a transgenic (tg) mouse line expressing the human N88S seipin mutant with the murine Thy-1 promoter to permit analyses of in vivo phenotypic changes. The N88S seipin tg mice develop a progressive spastic motor deficit, reactive gliosis in the spinal cord and neurogenic muscular atrophy, recapitulating the symptomatic and pathological phenotype in patients of seipinopathy. We also found that expression of mutant seipin in mice upregulated the ER stress marker, immunoglobulin-heavy-chain-binding protein, protein disulfide isomerase and X-box binding protein 1, but was not linked to significant neuronal loss in affected tissue, thereby indicating that ER stress is sufficient, while neuronal death is not necessary, for the development of motor phenotypes of seipinopathies. Our findings in the mutant seipin tg mouse provide clues to understand the relationship with ER stress and neurodegeneration, and the seipin tg mouse is a valid tool for the development of novel therapeutic strategies against ER stress-related diseases.
UR - http://www.scopus.com/inward/record.url?scp=80052726190&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052726190&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddr304
DO - 10.1093/hmg/ddr304
M3 - Article
C2 - 21750110
AN - SCOPUS:80052726190
VL - 20
SP - 3831
EP - 3840
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 19
M1 - ddr304
ER -