Mammalian uncoordinated 18-1 (MUNC18-1) is a synaptic protein that is crucial for fusion of synaptic vesicles with the pre-synaptic membrane, and thus the exocytosis of neurotransmitters. As well as its binding partner syntaxin-1, which also participates in exocytosis, MUNC18-1 regulates the stability of endocytosis proteins, including dynamin-1, which is downregulated in MUNC18-1-null mouse brains. In this study, Matthijs Verhage and colleagues (Lammertse et al., 2022) characterise the effects of MUNC18-1 knockout (KO) in neurons on dynamin-1 levels, showing an 80% reduction in protein and 50% reduction in mRNA transcript levels. However, this dependency is not reciprocal, since KO of dynamin-1, -2 or -3 did not affect MUNC18-1 levels. Despite reduced dynamin-1 levels, endocytosis of cell surface receptors is only perturbed in a cargo-specific manner, where uptake of transferrin, but not cholera toxin B (CTB), is reduced. Additionally, reduced dynamin-1 levels do not explain the neurodegeneration seen in MUNC-18-1 KO cells, which are not rescued by dynamin-1 overexpression. Together, these findings suggest that although MUNC18-1 does affect the stability of dynamin-1, other as-yet-unidentified factors must be at play that can explain the neurodegeneration of MUNC-18-1 KO neurons. However, it highlights that MUNC18-1 is not only involved in exocytosis, but also regulates the protein and mRNA levels of other pre-synaptic endocytosis genes.
