title: Amyotrophic lateral sclerosis-related VAPB P56S mutation differentially affects the function and survival of corticospinal and spinal motor neurons.
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) mice that heterologously express human wild-type (WT) and P56S VAPB under the control of a 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 provide new pathophysiological mechanisms of P56S VAPB that differentially affect the function and survival of CSMNs and SMNs in ALS8.
authors.affiliation: Transgenics Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA and.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Aliaga
authors.forename: Chen
authors.initials: C
authors.lastname: Lai
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: Nikolai
authors.initials: N
authors.lastname: Chub
authors.forename: Hoon
authors.initials: H
authors.lastname: Shim
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.forename: Chengsong
authors.initials: C
authors.lastname: Xie
authors.forename: Wan-Jou
authors.initials: WJ
authors.lastname: Yang
authors.forename: Xian
authors.initials: X
authors.lastname: Lin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Donovan
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
mesh_terms: D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002470:Cell Survival; D003712:Dendrites / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity; D009046:Motor Neurons / Q000473:pathology / Q000502:physiology*; D020125:Mutation, Missense; D009410:Nerve Degeneration / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000502:physiology; D011392:Proline / Q000235:genetics; D012694:Serine / Q000235:genetics; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology*; D056811:Unfolded Protein Response; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C496748:VAPB protein, human; D033921:Vesicular Transport Proteins; D012694:Serine; D011392:Proline