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bioRxiv · 10.1101/2021.12.14.472444

Loss of Activity-Induced Mitochondrial ATP Production Underlies the Synaptic Defects in a Drosophila model of ALS

Karagas, N. E.·Tan, K. L.·Bellen, H. J.·Venkatachalam, K.·Wong, C.-O.
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Abstract

Mutations in the gene encoding VAPB (vesicle-associated membrane protein B) cause a familial form of Amyotrophic Lateral Sclerosis (ALS). Expression of an ALS-related variant of vapb (vapbP58S) in Drosophila motor neurons results in morphological 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 morphological changes, a mechanism for the loss of presynaptic microtubules has been lacking. Here, we demonstrate the suppression of vapbP58S- induced changes in NMJ morphology by either the loss of ER Ca2+ release channels or the inhibition Ca2+/calmodulin (CaM)-activated kinase II (CaMKII). These data suggest a model in which decreased stability of presynaptic microtubules at vapbP58S NMJs result from hyperactivation of CaMKII due to elevated cytosolic [Ca2+]. We attribute the Ca2+ dyshomeostasis to delayed extrusion of cytosolic Ca2+ stemming from a paucity of activity-induced mitochondrial ATP production coupled with elevated rates of ATP consumption. Taken together, our data point to bioenergetic dysfunction as the root cause for the synaptic defects in vapbP58S-expressing Drosophila motor neurons. Significance StatementRates of ATP production and consumption are tightly synchronized in healthy neurons. Whether this synchrony is lost in models of neurodegenerative diseases remains poorly understood. Here, we find that expression of a gene encoding an ALS-causing variant of an ER membrane protein, VAPB, decouples mitochondrial ATP production from neuronal activity. Due to a combination of diminished ATP production and elevated ATP consumption -- established outcomes in ALS neurons -- the levels of ATP in vapbP58S neurons are unable to keep up with the bioenergetic burden of depolarization. The resulting paucity of ATP and attendant decrease in the activity of Ca2+ ATPases results in diminished extrusion of cytosolic Ca2+ in vapbP58S-expressing motor neurons. The accumulation of residual Ca2+ in vapbP58S-expressing neurons underlies paired-pulse facilitation of synaptic vesicle release, and the changes in bouton development at the NMJ. In summary, our findings point to bioenergetic dysfunction due to the loss of activity-induced ATP production as being the cause of the synaptic defects observed in a Drosophila model of ALS.

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Karagas, N. E., Tan, K. L., Bellen, H. J., Venkatachalam, K., Wong, C.-O.. 2021-12-16. Loss of Activity-Induced Mitochondrial ATP Production Underlies the Synaptic Defects in a Drosophila model of ALS. https://doi.org/10.1101/2021.12.14.472444

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