Abstract
The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) has been linked to an atypical autosomal dominant form of familial amyotrophic lateral sclerosis 8 (ALS8). To investigate the pathogenic mechanism of P56S VAPB in ALS, we generated transgenic (Tg) micethat heterologously expresshumanwild-type (WT)andP56SVAPBunder the control ofa pan-neuronal promoter Thy1.2. While WT VAPB Tg mice did not exhibit any overt motor behavioral phenotypes, P56S VAPB Tg mice developed progressive hyperactivities and other motor abnormalities. VAPB protein was accumulated as large punctate in the soma and proximal dendrites of both corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs) in P56S VAPB Tg mice. Concomitantly, a significant increase of endoplasmic reticulum stress and unfolded protein response and the resulting up-regulation of pro-apoptotic factor CCAAT/enhancer-binding protein homologous protein expression were observed in the CSMNs and SMNs of P56S VAPB Tg mice. However, only a progressive loss of CSMNs but not SMNs was found in P56S VAPB Tg mice. In SMNs, P56S VAPB promoted a rather selective translocation of VAPB protein onto the postsynaptic site of C-boutons that altered the morphology of C-boutons and impaired the spontaneous rhythmic discharges of SMNs. Therefore, these findings providenewpathophysiological mechanisms ofP56SVAPBthat differentially affect the function and survival of CSMNs and SMNs in ALS8.
| Original language | English (US) |
|---|---|
| Article number | ddt279 |
| Pages (from-to) | 4293-4305 |
| Number of pages | 13 |
| Journal | Human Molecular Genetics |
| Volume | 22 |
| Issue number | 21 |
| DOIs | |
| State | Published - Nov 2013 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
- Molecular Biology
Cite this
Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons. / Aliaga, Leonardo; Lai, Chen; Yu, Jia; Chub, Nikolai; Shim, Hoon; Sun, Lixin; Xie, Chengsong; Yang, Wan Jou; Lin, Xian; O'Donovan, Michael J.; Cai, Huaibin.
In: Human Molecular Genetics, Vol. 22, No. 21, ddt279, 11.2013, p. 4293-4305.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons
AU - Aliaga, Leonardo
AU - Lai, Chen
AU - Yu, Jia
AU - Chub, Nikolai
AU - Shim, Hoon
AU - Sun, Lixin
AU - Xie, Chengsong
AU - Yang, Wan Jou
AU - Lin, Xian
AU - O'Donovan, Michael J.
AU - Cai, Huaibin
PY - 2013/11
Y1 - 2013/11
N2 - The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) has been linked to an atypical autosomal dominant form of familial amyotrophic lateral sclerosis 8 (ALS8). To investigate the pathogenic mechanism of P56S VAPB in ALS, we generated transgenic (Tg) micethat heterologously expresshumanwild-type (WT)andP56SVAPBunder the control ofa pan-neuronal promoter Thy1.2. While WT VAPB Tg mice did not exhibit any overt motor behavioral phenotypes, P56S VAPB Tg mice developed progressive hyperactivities and other motor abnormalities. VAPB protein was accumulated as large punctate in the soma and proximal dendrites of both corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs) in P56S VAPB Tg mice. Concomitantly, a significant increase of endoplasmic reticulum stress and unfolded protein response and the resulting up-regulation of pro-apoptotic factor CCAAT/enhancer-binding protein homologous protein expression were observed in the CSMNs and SMNs of P56S VAPB Tg mice. However, only a progressive loss of CSMNs but not SMNs was found in P56S VAPB Tg mice. In SMNs, P56S VAPB promoted a rather selective translocation of VAPB protein onto the postsynaptic site of C-boutons that altered the morphology of C-boutons and impaired the spontaneous rhythmic discharges of SMNs. Therefore, these findings providenewpathophysiological mechanisms ofP56SVAPBthat differentially affect the function and survival of CSMNs and SMNs in ALS8.
AB - The substitution of Proline with Serine at residue 56 (P56S) of vesicle-associated membrane protein-associated protein B (VAPB) has been linked to an atypical autosomal dominant form of familial amyotrophic lateral sclerosis 8 (ALS8). To investigate the pathogenic mechanism of P56S VAPB in ALS, we generated transgenic (Tg) micethat heterologously expresshumanwild-type (WT)andP56SVAPBunder the control ofa pan-neuronal promoter Thy1.2. While WT VAPB Tg mice did not exhibit any overt motor behavioral phenotypes, P56S VAPB Tg mice developed progressive hyperactivities and other motor abnormalities. VAPB protein was accumulated as large punctate in the soma and proximal dendrites of both corticospinal motor neurons (CSMNs) and spinal motor neurons (SMNs) in P56S VAPB Tg mice. Concomitantly, a significant increase of endoplasmic reticulum stress and unfolded protein response and the resulting up-regulation of pro-apoptotic factor CCAAT/enhancer-binding protein homologous protein expression were observed in the CSMNs and SMNs of P56S VAPB Tg mice. However, only a progressive loss of CSMNs but not SMNs was found in P56S VAPB Tg mice. In SMNs, P56S VAPB promoted a rather selective translocation of VAPB protein onto the postsynaptic site of C-boutons that altered the morphology of C-boutons and impaired the spontaneous rhythmic discharges of SMNs. Therefore, these findings providenewpathophysiological mechanisms ofP56SVAPBthat differentially affect the function and survival of CSMNs and SMNs in ALS8.
UR - http://www.scopus.com/inward/record.url?scp=84885734944&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885734944&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddt279
DO - 10.1093/hmg/ddt279
M3 - Article
C2 - 23771029
AN - SCOPUS:84885734944
VL - 22
SP - 4293
EP - 4305
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 21
M1 - ddt279
ER -