title: Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment.
abstract: BACKGROUND
  Protein aggregation and the formation of intracellular inclusions are a central feature of many neurodegenerative disorders, but precise knowledge about their pathogenic role is lacking in most instances. Here we have characterized inclusions formed in transgenic mice carrying the P56S mutant form of VAPB that causes various motor neuron syndromes including ALS8.
  
  
  RESULTS
  Inclusions in motor neurons of VAPB-P56S transgenic mice are characterized by the presence of smooth ER-like tubular profiles, and are immunoreactive for factors that operate in the ER associated degradation (ERAD) pathway, including p97/VCP, Derlin-1, and the ER membrane chaperone BAP31. The presence of these inclusions does not correlate with signs of axonal and neuronal degeneration, and axotomy leads to their gradual disappearance, indicating that they represent reversible structures. Inhibition of the proteasome and knockdown of the ER membrane chaperone BAP31 increased the size of mutant VAPB inclusions in primary neuron cultures, while knockdown of TEB4, an ERAD ubiquitin-protein ligase, reduced their size. Mutant VAPB did not codistribute with mutant forms of seipin that are associated with an autosomal dominant motor neuron disease, and accumulate in a protective ER derived compartment termed ERPO (ER protective organelle) in neurons.
  
  
  CONCLUSIONS
  The data indicate that the VAPB-P56S inclusions represent a novel reversible ER quality control compartment that is formed when the amount of mutant VAPB exceeds the capacity of the ERAD pathway and that isolates misfolded and aggregated VAPB from the rest of the ER. The presence of this quality control compartment reveals an additional level of flexibility of neurons to cope with misfolded protein stress in the ER.
authors.affiliation: Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands. c.hoogenraad@uu.nl.
authors.forename: Marijn
authors.initials: M
authors.lastname: Kuijpers
authors.forename: Vera
authors.initials: V
authors.lastname: van Dis
authors.forename: Elize D
authors.initials: ED
authors.lastname: Haasdijk
authors.forename: Martin
authors.initials: M
authors.lastname: Harterink
authors.forename: Karin
authors.initials: K
authors.lastname: Vocking
authors.forename: Jan A
authors.initials: JA
authors.lastname: Post
authors.forename: Wiep
authors.initials: W
authors.lastname: Scheper
authors.forename: Casper C
authors.initials: CC
authors.lastname: Hoogenraad
authors.forename: Dick
authors.initials: D
authors.lastname: Jaarsma
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001369:Axons / Q000502:physiology / Q000648:ultrastructure; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000502:physiology* / Q000648:ultrastructure; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006624:Hippocampus / Q000503:physiopathology / Q000648:ultrastructure; D002479:Inclusion Bodies / Q000502:physiology* / Q000648:ultrastructure; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000502:physiology* / Q000648:ultrastructure; D009154:Mutation; D051381:Rats; D012584:Sciatic Nerve / Q000293:injuries / Q000503:physiopathology / Q000648:ultrastructure; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C496748:VAPB protein, human; D033921:Vesicular Transport Proteins