VAP-B(P56S)-associated ALS induces the formation of karmellea
Multilamellar ER-derived membrane structures called ‘Karmellea’ were associated with VAP-B(P56S) as reported by Gkogkas et al., J. Neurochem. 2011
ALS
Insoluble Aggregates of VAP-B(P56S) Protein Induce Neurotoxic Effects
To demonstrate the correlation between aggregate formation and cell viability, we compared the effect of VAP-B(WT), the P56S mutant, and the P56S/DCC/II mutant on Neuro2a (N2a) cell viability using the MTT assay. We found that the VAP-B(P56S) mutant reduced N2a… Continue Reading
p56S Insoluble Aggregates
Characterization of p56S insoluble aggregates. Analysis of the solubilization of the indicated mutants suggest that the oligomerization of VAP-B(P56S) is mediated mainly by the coiled-coil domain and that the GXXXG also contributes to VAP-B(P56S) oligomerization and consequently for the production… Continue Reading
The Effect of the P56S on FFAT Binding
Oligomerization of VAP-B(P56S) prevents binding of FFAT proteins. We found that the conformational changes of MSP domain of P56S mutant have no direct effect on FFAT-binding. Rather, they enhance VAP-B(P56S) oligomerization driven by the combined contributions of the coiled-coil and… Continue Reading
The P56S Induces Conformational Changes of the MSP Domain
The P56S mutation induces the exposure of hydrophobic patches, thereby facilitating MSP oligomerization. To better understand how the P56S mutation enhances oligomerization of VAP-B(P56S), we characterized the folding properties of recombinant purified MSP domains of the WT and P56S mutant,… Continue Reading
The N-terminal Cytoplasmic MSP (Major Sperm Protein) Domain
The N-terminal cytoplasmic MSP (major sperm protein) domain of VAP-B consistes of 125 amino acids (aa), and a coiled-coil domain (CCD) of ~50 aa. Proline 56 resides within a highly conserved sequence of 16 aa in the MSP domain in… Continue Reading
Structural requirements for VAP-B oligomerization and their implication in Als-associated VAP-B (P56S) neurotoxicity
We defined the structural requirements for VAP-B oligomerization and demonstrated their contribution for VAP-B(P56S) aggregation and neurotoxicity. We show that the oligomerization of VAP-B is mainly mediated by its coiled-coil domain, and that the GXXXG dimerization motif within the transmembrane… Continue Reading
Potential Mechanisms Underlying the Disease
Potential mechanisms underlying the aggregation and motor neurodegeneration of VAP-B (P56S) mutant.
The Underlying Mechanism of VAP-B
Expression of the VAP-B(P56S) mutant in cultured cells results in the formation of insoluble protein aggregates. These aggregates might induce loss-of-function of wild-type VAP-B protein, gain of toxic function, or both.
Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS) is a motor neurone disease (MND) characterized by death of motor neurons in the cerebral cortex, brain stem, and spinal cord. ALS is one of the most common adult motor neuron diseases that, at present, has no cure or effective… Continue Reading
