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Featured ArticleResearch Articles, Neurobiology of Disease

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

Nicholas E. Karagas, Richa Gupta, Elham Rastegari, Kai Li Tan, Ho Hang Leung, Hugo J. Bellen, Kartik Venkatachalam and Ching-On Wong
Journal of Neuroscience 19 October 2022, 42 (42) 8019-8037; DOI: https://doi.org/10.1523/JNEUROSCI.2456-21.2022
Nicholas E. Karagas
1Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center, Houston, Texas 77030
5Graduate Program in Biochemistry and Cell Biology, MD Anderson Cancer Center and University of Texas Health Sciences Center Graduate School of Biomedical Sciences, Houston, TX, 77030
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Richa Gupta
1Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center, Houston, Texas 77030
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Elham Rastegari
1Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center, Houston, Texas 77030
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Kai Li Tan
2Departments of Molecular and Human Genetics and Neuroscience, Baylor College of Medicine, Houston, TX 77030
3Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030
4Duncan Neurological Research Institute, Texas Children Hospital, Houston, Texas 77030
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Ho Hang Leung
7Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102
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Hugo J. Bellen
2Departments of Molecular and Human Genetics and Neuroscience, Baylor College of Medicine, Houston, TX 77030
3Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030
4Duncan Neurological Research Institute, Texas Children Hospital, Houston, Texas 77030
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Kartik Venkatachalam
1Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Sciences Center, Houston, Texas 77030
5Graduate Program in Biochemistry and Cell Biology, MD Anderson Cancer Center and University of Texas Health Sciences Center Graduate School of Biomedical Sciences, Houston, TX, 77030
6Graduate Program in Neuroscience, MD Anderson Cancer Center and University of Texas Health Sciences Center Graduate School of Biomedical Sciences, Houston, TX, 77030
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Ching-On Wong
7Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102
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Abstract

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 vapb (vapbP58S) in Drosophila 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 vapbP58S-induced changes in NMJ morphology by either a loss of endoplasmic reticulum (ER) Ca2+ release channels or the inhibition Ca2+/calmodulin (CaM)-activated kinase II (CaMKII). These data suggest that decreased stability of presynaptic microtubules at vapbP58S NMJs results from hyperactivation of CaMKII because of elevated cytosolic [Ca2+]. We attribute the Ca2+ dyshomeostasis to delayed extrusion of cytosolic Ca2+. Suggesting that this defect in Ca2+ extrusion arose from an insufficient response to the bioenergetic demand of neural activity, depolarization-induced mitochondrial ATP production was diminished in vapbP58S neurons. These findings point to bioenergetic dysfunction as a potential cause for the synaptic defects in vapbP58S-expressing motor neurons.

SIGNIFICANCE STATEMENT 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 Ca2+ extrusion, which could result from insufficient energy to power Ca2+ ATPases, results in the accumulation of residual Ca2+ 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.

  • ALS
  • Drosophila neurobiology
  • ER calcium channels
  • mitochondrial ATP production
  • neurodegeneration
  • VAPB

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The Journal of Neuroscience: 42 (42)
Journal of Neuroscience
Vol. 42, Issue 42
19 Oct 2022
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Loss of Activity-Induced Mitochondrial ATP Production Underlies the Synaptic Defects in a Drosophila Model of ALS
Nicholas E. Karagas, Richa Gupta, Elham Rastegari, Kai Li Tan, Ho Hang Leung, Hugo J. Bellen, Kartik Venkatachalam, Ching-On Wong
Journal of Neuroscience 19 October 2022, 42 (42) 8019-8037; DOI: 10.1523/JNEUROSCI.2456-21.2022

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Loss of Activity-Induced Mitochondrial ATP Production Underlies the Synaptic Defects in a Drosophila Model of ALS
Nicholas E. Karagas, Richa Gupta, Elham Rastegari, Kai Li Tan, Ho Hang Leung, Hugo J. Bellen, Kartik Venkatachalam, Ching-On Wong
Journal of Neuroscience 19 October 2022, 42 (42) 8019-8037; DOI: 10.1523/JNEUROSCI.2456-21.2022
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Keywords

  • ALS
  • Drosophila neurobiology
  • ER calcium channels
  • mitochondrial ATP production
  • neurodegeneration
  • VAPB

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