Next up is Helen Miranda discussing "Increased p4EBP1 underlies ALS pathology associated to P56S mutant VAPB" #ASHG20
ALS is the most common adult-onset neurodegenerative disorder. 50% of patients do not survive beyond third year of diagnosis. Pathophysiology across upper and lower motor neurones. 90% of cases are sporadic in presentation. #ASHG20
Mutations in >25 genes have been associated in ALS. Focus on VAPB. Highly conserved gene that is ubiquitously expression. P56S mutation is the causative gene for ALS type 8 - mostly identified in Brazilian population, but has been identified globally. #ASHG20
Protein has broader association to other types of ALS including ALS1 and other forms of sporadic ALS. #ASHG20
VAPB mediates diverse intracellular functions including ER stress, lipid transfer, vesicle transport and autophagy #ASHG20
HM lab models ALS in iPSCs. Began with unbiased interactome approach to find binding partners. Interactome is associated with mRNA translation and mTOR #ASHG20
mTOR controls translation through phosphorylation of 4EBP1, which acts on eIF4E. Phosphorylation of 4EBP1 is dysregulated in ALS8-NPCs [neural progenitor cells]. 4EBP1 and p4EBP1 are dysregulated in ALS8 motor neurons, which have altered mRNA translation #ASHG20
ALS8 motor neurons show mitochondrial dysregulation when exposed to FCCP. Motor neuron activity is also reduced compared to controls - initially hyperactive before maturation, activity appears to plateau earlier in maturation compared to controls #ASHG20
• • •
Missing some Tweet in this thread? You can try to
force a refresh
