SNAREopathies: Diversity in Mechanisms and Symptoms

Neuronal SNAREs and their key regulators together drive synaptic vesicle exocytosis and synaptic transmission as a single integrated membrane fusion machine. Human pathogenic mutations have now been reported for all eight core components, but patients are diagnosed with very different neurodevelopmental syndromes. We propose to unify these syndromes, based on etiology and mechanism, as SNAREopathies.'' Here, we review the strikingly diverse clinical phenomenology and disease severity and the also remarkably diverse genetic mechanisms. We argue that disease severity generally scales with functional redundancy and, conversely, that the large effect of mutations in some SNARE genes is the price paid for extensive integration and exceptional specialization. Finally, we discuss how subtle differences in components being rate limiting in different types of neurons helps to explain the main symptoms.