Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

Abstract

Mitochondria are key regulators of cell viability and provide essential functions that protect against neurodegenerative disease. To develop a model for mitochondrial-dependent neurodegeneration in Caenorhabditis elegans, we used RNA interference (RNAi) and genetic ablation to knock down expression of enzymes in the Coenzyme Q (CoQ) biosynthetic pathway. CoQ is a required component of the ATP-producing electron transport chain in mitochondria. We found that reduced levels of CoQ result in a progressive uncoordinated (Unc) phenotype that is correlated with the appearance of degenerating GABA neurons. Both the Unc and degenerative phenotypes emerge during late larval development and progress in adults. Neuron classes in motor and sensory circuits that use other neurotransmitters (dopamine, acetylcholine, glutamate, serotonin) and body muscle cells were less sensitive to CoQ depletion. Our results indicate that the mechanism of GABA neuron degeneration is calcium-dependent and requires activation of the apoptotic gene, ced-4 (Apaf-1). A molecular cascade involving mitochondrial-initiated cell death is also consistent with our finding that GABA neuron degeneration requires the mitochondrial fission gene, drp-1. We conclude that the cell selectivity and developmental progression of CoQ deficiency in C. elegans indicate that this model may be useful for delineating the role of mitochondrial dysfunction in neurodegenerative disease.cell death | disease | mitochondria | neurodegeneration | necrosis

Invertebrate Models for Coenzyme Q₁₀ Deficiency

“…This uncoordinated phenotype emerges during late larval development, progresses in adulthood, and proceeds with a selective cell death pathway activation where apoptotic and mitochondrial fission genes take part, which is a clear signal of initiation of a mitophagy process within these cells as in humans [Rodríguez-Hernández et al, 2009;Cotan et al, 2011]. However, neurons and body muscle cells that use other neurotransmitters, such as dopamine, acetylcholine, serotonin, or glutamate, were more resistant to CoQ depletion [Earls et al, 2010]. Similar phenotypes were described within the same work for knockdown of the genes coq-2 and coq-3.…”

“…First generation of coq-1 mutants are sterile and present both morphological defects and improper development of the organs [Gavilan et al, 2005]. Also, knockdown of coq-1 by feeding bacteria producing RNAi against this gene results in the progressive degeneration of GABA neurons and age-dependent loss of motor coordination [Earls et al, 2010]. This uncoordinated phenotype emerges during late larval development, progresses in adulthood, and proceeds with a selective cell death pathway activation where apoptotic and mitochondrial fission genes take part, which is a clear signal of initiation of a mitophagy process within these cells as in humans [Rodríguez-Hernández et al, 2009;Cotan et al, 2011].…”

An Overview of Current Mouse Models Recapitulating Coenzyme Q₁₀ Deficiency Syndrome

“…Mol Syndromol 2014;5:180-186 DOI: 10.1159/000362942 182 than others to CoQ ablation [Earls et al, 2010]. Moreover, the study of Drosophila melanogaster carrying mutations in qless , homolog of PDSS1 , suggested that CoQ promotes the growth of neuroblast lineages, protecting neural cells against mitochondrial stress and apoptosis [Grant et al, 2010].…”

Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

“…Using C. elegans transgenics that express mutant TDP-43 or FUS or FUS[S57D], referred to herein as mTDP-43 and mFUS respectively) in motor neurons [15] we evaluated the efficacy of these models as drug discovery tools by testing three compounds with known clinically neuroprotective properties: lithium chloride, MB and riluzole [18,19]. The mTDP-43 and mFUS transgenic worms show adult-onset, progressive motility defects leading to paralysis when grown under standard laboratory conditions on solid agar plates over the course of 10 to 12 days [15].…”

“…Additionally, the paralysis assay is widely used to study age-dependent degenerative phenotypes and is not observed in wild type non-transgenic worms until they reach advanced age (approximately 20 days) [16][17][18]. Finally, motility defects and adult onset paralysis have been previously observed in worms with degenerating GABAergic motor neurons suggesting that mTDP-43 and mFUS may negatively affect GABAergic neuronal function and survival [19]. …”