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Vexed mutations promote degeneration of dopaminergic neurons through excessive activation of the innate immune response.

ABSTRACT: The hallmark of Parkinson's disease (PD) is the loss of dopaminergic (DA) neurons in the brain. However, little is known about why DA neurons are selectively vulnerable to PD. We previously completed a screen identifying genes associated with the progressive degeneration of DA neurons. Here we describe the role of a previously uncharacterized gene, CG42339, in the loss of DA neurons using Drosophila Melanogaster. CG42339 mutants display a progressive loss of DA neurons and locomotor dysfunction, along with an accumulation of advanced glycation end products (AGEs) in the brain. Based on this phenotype, we refer to CG42339 as vexed. We demonstrate that vexed is specifically required within cortex glia to maintain neuronal viability. Loss of vexed function results in excessive activation of the innate immune response in the brain, leading to loss of DA neurons. We show that activation of the innate immune response leads to increased nitric oxide signaling and accumulation of AGEs, which ultimately result in neurodegeneration. These results provide further insight into the relationship between the role of the immune response in the central nervous system and how this impacts neuronal viability.

SUBMITTER: Davis J

PROVIDER: S-EPMC9630459 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Vexed mutations promote degeneration of dopaminergic neurons through excessive activation of the innate immune response.

Davis Jacinta J Kolaski Elizabeth E Babcock Daniel T DT

NPJ Parkinson's disease 20221102 1

The hallmark of Parkinson's disease (PD) is the loss of dopaminergic (DA) neurons in the brain. However, little is known about why DA neurons are selectively vulnerable to PD. We previously completed a screen identifying genes associated with the progressive degeneration of DA neurons. Here we describe the role of a previously uncharacterized gene, CG42339, in the loss of DA neurons using Drosophila Melanogaster. CG42339 mutants display a progressive loss of DA neurons and locomotor dysfunction, ...[more]

PMID: 36323700

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Project description:Charcot-Marie-Tooth disease is a chronic hereditary motor and sensory polyneuropathy targeting Schwann cells and/or motor neurons. Its multifactorial and polygenic origin portrays a complex clinical phenotype of the disease with a wide range of genetic inheritance patterns. The disease-associated gene GDAP1 encodes for a mitochondrial outer membrane protein. Mouse and insect models with mutations in Gdap1 have reproduced several traits of the human disease. However, the precise function in the cell types affected by the disease remains unknown. Here, we use induced-pluripotent stem cells derived from a Gdap1 knockout mouse model to better understand the molecular and cellular phenotypes of the disease caused by the loss-of-function of this gene. Gdap1-null motor neurons display a fragile cell phenotype prone to early degeneration showing (1) altered mitochondrial morphology, with an increase in the fragmentation of these organelles, (2) activation of autophagy and mitophagy, (3) abnormal metabolism, characterized by a downregulation of Hexokinase 2 and ATP5b proteins, (4) increased reactive oxygen species and elevated mitochondrial membrane potential, and (5) increased innate immune response and p38 MAP kinase activation. Our data reveals the existence of an underlying Redox-inflammatory axis fueled by altered mitochondrial metabolism in the absence of Gdap1. As this biochemical axis encompasses a wide variety of druggable targets, our results may have implications for developing therapies using combinatorial pharmacological approaches and improving therefore human welfare. A Redox-immune axis underlying motor neuron degeneration caused by the absence of Gdap1. Our results show that Gdap1-/- motor neurons have a fragile cellular phenotype that is prone to degeneration. Gdap1-/- iPSCs differentiated into motor neurons showed an altered metabolic state: decreased glycolysis and increased OXPHOS. These alterations may lead to hyperpolarization of mitochondria and increased ROS levels. Excessive amounts of ROS might be the cause of increased mitophagy, p38 activation and inflammation as a cellular response to oxidative stress. The p38 MAPK pathway and the immune response may, in turn, have feedback mechanisms, leading to the induction of apoptosis and senescence, respectively. CAC, citric acid cycle; ETC, electronic transport chain; Glc, glucose; Lac, lactate; Pyr, pyruvate.

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Vexed mutations promote degeneration of dopaminergic neurons through excessive activation of the innate immune response.

Publications

Vexed mutations promote degeneration of dopaminergic neurons through excessive activation of the innate immune response.

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