Loss of Activity-Induced Mitochondrial ATP Production Underlies the Synaptic Defects in a Model of ALS.

Mutations in the gene encoding vesicle-associated membrane protein B (VAPB) cause a familial form of amyotrophic lateral sclerosis (ALS). Expression of an ALS-related variant of ( ) in motor neurons results in morphologic changes at the larval neuromuscular junction (NMJ) characterized by the appearance of fewer, but larger, presynaptic boutons. Although diminished microtubule stability is known to underlie these morphologic changes, a mechanism for the loss of presynaptic microtubules has been lacking. By studying flies of both sexes, we demonstrate the suppression of -induced changes in NMJ morphology by either a loss of endoplasmic reticulum (ER) Ca release channels or the inhibition Ca/calmodulin (CaM)-activated kinase II (CaMKII). These data suggest that decreased stability of presynaptic microtubules at NMJs results from hyperactivation of CaMKII because of elevated cytosolic [Ca]. We attribute the Ca dyshomeostasis to delayed extrusion of cytosolic Ca Suggesting that this defect in Ca extrusion arose from an insufficient response to the bioenergetic demand of neural activity, depolarization-induced mitochondrial ATP production was diminished in neurons. These findings point to bioenergetic dysfunction as a potential cause for the synaptic defects in -expressing motor neurons. Whether the synchrony between the rates of ATP production and demand is lost in degenerating neurons remains poorly understood. We report that expression of a gene equivalent to an amyotrophic lateral sclerosis (ALS)-causing variant of vesicle-associated membrane protein B (VAPB) in fly neurons decouples mitochondrial ATP production from neuronal activity. Consequently, levels of ATP in mutant neurons are unable to keep up with the bioenergetic burden of neuronal activity. Reduced rate of Ca extrusion, which could result from insufficient energy to power Ca ATPases, results in the accumulation of residual Ca in mutant neurons and leads to alterations in synaptic vesicle (SV) release and synapse development. These findings suggest that synaptic defects in a model of ALS arise from the loss of activity-induced ATP production.