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The Journal of Neuroscience, September 5, 2007, 27(36):9801-9815; doi:10.1523/JNEUROSCI.2661-07.2007

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Neurobiology of Disease
Motor Neuron Disease-Associated Mutant Vesicle-Associated Membrane Protein-Associated Protein (VAP) B Recruits Wild-Type VAPs into Endoplasmic Reticulum-Derived Tubular Aggregates

Eva Teuling,¹ Suaad Ahmed,¹ Elize Haasdijk,¹ Jeroen Demmers,² Michel O. Steinmetz,⁴ Anna Akhmanova,³ Dick Jaarsma,¹ and Casper C. Hoogenraad¹

Departments of ¹Neuroscience, ²Biochemistry, ³Cell Biology and Genetics, Erasmus Medical Center, 3000CA Rotterdam, The Netherlands, and ⁴Biomolecular Research, Structural Biology, Paul Scherrer Institut, CH-5232 Villigen, Switzerland

Correspondence should be addressed to either Casper C. Hoogenraad or Dick Jaarsma, Department of Neuroscience, Erasmus Medical Center, P.O. Box 2040, 3000CA, Rotterdam, The Netherlands. Email: c.hoogenraad{at}erasmusmc.nl or Email: d.jaarsma{at}erasmusmc.nl

The vesicle-associated membrane protein-associated proteins (VAPs) VAPA and VAPB interact with lipid-binding proteins carrying a short motif containing two phenylalanines in an acidic tract (FFAT motif) and targets them to the cytosolic surface of the endoplasmic reticulum (ER). A genetic mutation (P56S) in the conserved major sperm protein homology domain of VAPB has been linked to motor-neuron degeneration in affected amyotrophic lateral sclerosis (ALS) patients. We report that in the CNS, VAPB is abundant in motor neurons and that the P56S substitution causes aggregation of mutant VAPB in immobile tubular ER clusters, perturbs FFAT-motif binding, and traps endogenous VAP in mutant aggregates. Expression of mutant VAPB or reduction of VAP by short hairpin RNA in primary neurons causes Golgi dispersion and cell death. VAPA and VAPB are reduced in human ALS patients and superoxide dismutase 1 (SOD1)-ALS-transgenic mice, suggesting that VAP family proteins may be involved in the pathogenesis of sporadic and SOD1-linked ALS. Our data support a model in which reduced levels of VAP family proteins result in decreased ER anchoring of lipid-binding proteins and cause motor neuron degeneration.

Key words: protein aggregation disease; amyotrophic lateral sclerosis; ALS; endoplasmic reticulum; lipid-binding protein; VAP family proteins; motor neuron disease

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Received June 12, 2007; revised July 30, 2007; accepted Aug. 1, 2007.

Correspondence should be addressed to either Casper C. Hoogenraad or Dick Jaarsma, Department of Neuroscience, Erasmus Medical Center, P.O. Box 2040, 3000CA, Rotterdam, The Netherlands. Email: c.hoogenraad{at}erasmusmc.nl or Email: d.jaarsma{at}erasmusmc.nl

This article has been cited by other articles:

				C. Gkogkas, S. Middleton, A. M. Kremer, C. Wardrope, M. Hannah, T. H. Gillingwater, and P. Skehel VAPB interacts with and modulates the activity of ATF6 Hum. Mol. Genet., June 1, 2008; 17(11): 1517 - 1526. [Abstract] [Full Text] [PDF]

				M. Hirano VAPB: New genetic clues to the pathogenesis of ALS Neurology, April 1, 2008; 70(14): 1161 - 1162. [Full Text] [PDF]

				A. Chai, J. Withers, Y. H. Koh, K. Parry, H. Bao, B. Zhang, V. Budnik, and G. Pennetta hVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction Hum. Mol. Genet., January 15, 2008; 17(2): 266 - 280. [Abstract] [Full Text] [PDF]

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