Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons

Leonardo Aliaga, Chen Lai, Jia Yu, Nikolai Chub, Hoon Shim, Lixin Sun, Chengsong Xie, Wan Jou Yang, Xian Lin, Michael J. O'Donovan, Huaibin Cai

    Research output: Contribution to journalArticle

    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 languageEnglish (US)
    Pages (from-to)4293-4305
    Number of pages13
    JournalHuman molecular genetics
    Volume22
    Issue number21
    DOIs
    StatePublished - Nov 2013

    ASJC Scopus subject areas

    • Molecular Biology
    • Genetics
    • Genetics(clinical)

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  • Cite this

    Aliaga, L., Lai, C., Yu, J., Chub, N., Shim, H., Sun, L., Xie, C., Yang, W. J., Lin, X., O'Donovan, M. J., & Cai, H. (2013). Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons. Human molecular genetics, 22(21), 4293-4305. https://doi.org/10.1093/hmg/ddt279