FIGURE 7.

Model depicting mechanisms linking ALS/FTD mutant C9orf72 with disruption of the VAPB‐PTPIP51 interaction, synaptic activity and neurodegeneration. C9orf72‐derived toxic DPRs activate GSK3β leading to breaking of the VAPB‐PTPIP51 tethers. This perturbs IP3 receptor‐mediated delivery of Ca²⁺ from ER to mitochondria to damage synaptic function and induce neurodegeneration. ALS/FTD linked TDP‐43 and FUS also disrupt the VAPB‐PTPIP51 interaction via activation of GSK3β (Stoica et al., 2014, 2016)