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Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment

Marijn Kuijpers12, Vera van Dis1, Elize D Haasdijk1, Martin Harterink2, Karin Vocking3, Jan A Post3, Wiep Scheper45, Casper C Hoogenraad12* and Dick Jaarsma1*

Author Affiliations

1 Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands

2 Division cell biology, Department Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands

3 Biomolecular Imaging, Faculty of Science, Dept. Biology, Utrecht University, Utrecht, The Netherlands

4 Department of Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

5 Department of Neurology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

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Acta Neuropathologica Communications 2013, 1:24  doi:10.1186/2051-5960-1-24

Published: 12 June 2013

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.

Keywords:
Amyotrophic lateral sclerosis (ALS); Protein aggregation; ER associated degradation; Motor neuron disease; Mouse model