Abstract
Sab (SH3 binding protein 5 or SH3BP5) is a mitochondrial scaffold protein involved in signaling associated with mitochondrial dysfunction and apoptosis; furthermore, Sab is a crucial signaling platform for neurodegenerative disease. To determine how this signaling nexus could have a significant effect on disease, we examined the regional abundance of Sab in the brain and sub-neuronal distribution, and we monitored the effect of Sab-mediated signaling on neuronal activity. We found that Sab is widely expressed in the adult mouse brain with increased abundance in hippocampus, ventral midbrain, and cerebellum. Sab was found in purified synaptosomes and in cultures of hippocampal neurons and astrocytes. Confocal and electron microscopy of mouse hippocampal sections confirmed the mitochondrial localization of Sab in the soma, dendrites, and axons. Given the localization and sub-neuronal distribution of Sab, we postulated that Sab-mediated signaling could affect neuronal function, so we measured the impact of inhibiting Sab-mediated events on the spontaneous activity in cultured hippocampal neurons. Treatment with a Sab-inhibitory peptide (Tat-SabKIM1), but not a scrambled control peptide, decreased the firing frequency and spike amplitudes. Our results demonstrate that brain-specific Sab-mediated signaling plays a role in neuronal activity through the manipulation of mitochondrial physiology by interacting kinases.