SNAP-25 Puts SNAREs at Center Stage in Metabolic Disease

Synaptosomal Associated Protein of 25 kD (SNAP-25) is an essential protein contributing 2 out of 4 α-helices in the formation of the core soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex which mediates regulated membrane fusion. Regulated exocytosis is a strictly controlled event in eukaryotic cells mediating important homeostatic processes and cellular communications. Altered release of neurotransmitters or hormones is usually considered as part of the progressing pathophysiology of central neurological or peripheral metabolic disorders. However, the molecular changes which precede and initiate disturbed secretion of neurotransmitters and hormones are still unclear. We have explored an alternative hypothesis; that a minor modification in the machinery mediating regulated exocytosis, instead, may underlie the origin of the diseases associated with altered secretion of neurotransmitters and hormones. Possibly, certain modifications to genes encoding for SNAREs or proteins affecting SNARE function may increase the susceptibility to develop disease and its progression can be accelerated when combined with aging and life style factors. To test this theory, we genetically manipulated the Snap25 gene to express only one of the two alternatively spliced isoforms, SNAP-25a. SNAP-25b-deficient mice demonstrated alterations in synaptic transmission and increased insulin secretion which, with time, spontaneously progressed into a pronounced metabolic disease, including defects in glucose homeostasis, obesity, liver steatosis and perturbations in central homeostatic signaling. Thus, deregulated function of SNAP-25 and possibly other SNAREs or SNARE-interacting proteins, can, by itself, act as risk factors for the development of metabolic disease. Here, we provide an overview of the peripheral and central consequences of the deregulations in core SNARE complex with focus on SNAP-25.