Fig. 8
From: Mechanism-based rescue of Munc18-1 dysfunction in varied encephalopathies by chemical chaperones
Model of Munc18-1 dysfunction in encephalopathies and rescue of deficits with chemical chaperones. Munc18-1-linked encephalopathies are caused by a dominant-negative disease mechanism. Heterozygous missense mutations in Munc18-1 cause a reduction in functional Munc18-1 levels significantly below 50%, due to accelerated degradation of misfolded mutant Munc18-1, aggregation of misfolded mutant Munc18-1 that is resistant to cellular clearance, and due to co-aggregation of WT Munc18-1. Chemical chaperones not only shift the unfolded–folded protein equilibrium significantly toward a folded state, but also result in an increase in total Munc18-1 levels. This overall increase in Munc18-1 levels and solubility is sufficient to rescue the Munc18-1-linked neuronal deficits in vitro and in vivo
