Motor neuron disease-associated mutant vesicle-associated membrane protein-associated protein (VAP) B recruits wild-type VAPs into endoplasmic reticulum-derived tubular aggregates.
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.
Teuling
Eva
E
Department of Neuroscience, Erasmus Medical Center, 3000CA Rotterdam, The Netherlands.
Ahmed
Suaad
S
Haasdijk
Elize
E
Demmers
Jeroen
J
Steinmetz
Michel O
MO
Akhmanova
Anna
A
Jaarsma
Dick
D
Hoogenraad
Casper C
CC
D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000473:pathology; D018014:Gene Transfer Techniques; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics* / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D013482:Superoxide Dismutase / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism*