Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms

Chung, Hyunglok; Wangler, Michael F.; Marcogliese, Paul C.; Jo, Ju-Yeon; Ravenscroft, Thomas A.; Zuo, Zhuang; Duraine, Lita; Sadeghzadeh, Sina; Li‐Kroeger, David; Schmidt, Robert E.; Pestronk, Alan; Rosenfeld, Jill A.; Burrage, Lindsay C.; Herndon, Mitchell J; Chen, Shan; Shillington, Amelle; Vawter-Lee, Marissa; Hopkin, Robert J.; Rodriguez-Smith, Jackeline; Henrickson, Michael; Lee, Brendan; Moser, Ann B.; Jones, Richard O.; Watkins, Paul A.; Yoo, Tae Kyung; Mar, Soe; Choi, Murim; Bucelli, Robert C.; Yamamoto, Shinya; Lee, Hyun Kyoung; Prada, Carlos E.; Chae, Jong‐Hee; Vogel, Tiphanie P.; Bellen, Hugo J.

doi:10.1016/j.neuron.2020.02.021

Cited by 79 publications

(91 citation statements)

References 109 publications

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“…The concept of neurons-glia communication via lipid metabolites has been advanced in specific forms of neurodegeneration (Chung et al, 2020;Liu et al, 2017). One therapeutic approach focused on the reduction of ROS, which are regarded as the upstream trigger of cell damage (Chung et al, 2020) (Ashibe and Motojima, 2009) and the PPARα agonist Bezafibrate has been suggested as an agent for treating Sjögren-Larsson Syndrome patients with partially inactivated FALDH (Gloerich et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans

Zeng

Preusch

et al. 2020

Preprint

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The intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjögren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, the C. elegans FALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS.

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Section: Discussionmentioning

confidence: 99%

Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans

Zeng

Preusch

et al. 2020

Preprint

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“…(4) Do the identified proteins/pathways provide opportunities for development of therapies and drug testing? Answering these questions can provide a diagnosis, link many genes to known pathways and processes, and identify drugs that can be tested in patients (Bellen et al, 2019;Chung et al, 2020;Yoon et al, 2017).…”

Section: Advances In Human Genetics Technologies and Rare Disease DImentioning

confidence: 99%

“…Indeed, research on Drosophila in the Model Organism Screening Center (MOSC) of the Undiagnosed Diseases Network (see below) and in collaboration with other human geneticists has provided diagnoses for more than 25 rare human genetic diseases in less than 4 years (Bellen et al, 2019;Wangler et al, 2017a;2017b). These include diseases caused by proteins associated with different organelles, such as mitochondria (Chao et al, 2017;Harel et al, 2016;Liu et al, 2017;Oláhová et al, 2018;Yoon et al, 2017), peroxisomes (Chao et al, 2016;Chung et al, 2020;Luo et al, 2017;Wangler et al, 2017b), lysosomes (Sȩntürk et al, 2019) and endosomes (Lin et al, 2018), as well as numerous developmental disorders (Ansar et al, 2018a;Ansar et al, 2018b;Link et al, 2019;Marcogliese et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases

Link

Bellen

2020

Development

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Next-generation sequencing has greatly accelerated the discovery of rare human genetic diseases. Nearly 45% of patients have variants associated with known diseases but the unsolved cases remain a conundrum. Moreover, causative mutations can be difficult to pinpoint because variants frequently map to genes with no previous disease associations and, often, only one or a few patients with variants in the same gene are identified. Model organisms, such as Drosophila, can help to identify and characterize these new disease-causing genes. Importantly, Drosophila allow quick and sophisticated genetic manipulations, permit functional testing of human variants, enable the characterization of pathogenic mechanisms and are amenable to drug tests. In this Spotlight, focusing on microcephaly as a case study, we highlight how studies of human genes in Drosophila have aided our understanding of human genetic disorders, allowing the identification of new genes in well-established signaling pathways.

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“…Loss-of-function mutations in ACOX1 result in neurodegeneration associated with developmental regression, recurrent seizures, exaggerated reflexes, loss of vision and hearing, and death between 4 and 10 years of age. Chung et al (2020) discover that a dominant, gain-of-function ACOX1 mutation also leads to neurological disease with hearing loss, gait instability caused by progressive damage to both sensory and motor peripheral nerve axons, and, eventually, CNS lesions. Interestingly, while the molecular pathogenesis caused by these two classes of ACOX1 mutations are very distinct, they both perturb the function of glia, a previously unsuspected player in ACOX1 dysregulation.…”

Section: Previewsmentioning

confidence: 99%

“…The loss of peroxisomal function has been implicated in many neurodegenerative diseases, yet the underlying molecular mechanisms are poorly understood. In this issue of Neuron, Chung et al (2020) demonstrate that gain-and loss-of-function mutations in the peroxisomal acyl-CoA oxidase 1 (ACOX1) gene cause neurodegeneration via distinct molecular pathways in glia.…”

mentioning

confidence: 99%

Lipid Metabolism and Axon Degeneration: An ACOX1 Balancing Act

Griffin

Ackerman

2020

Neuron

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Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms

Cited by 79 publications

References 109 publications

Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans

Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency inC. elegans

Using Drosophila to drive the diagnosis and understand the mechanisms of rare human diseases

Lipid Metabolism and Axon Degeneration: An ACOX1 Balancing Act

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