MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration

Ren, Mengda; Yang, Ying; Heng, Kelsey  Hwee Yee; Ng, Lu Yi; Chong, Claris Yuin-Yi; Ng, Yan Ting; Gorur-Shandilya, Srinivas; Lee, Rachel Min Qi; Lim, Kah Leong; Zhang, Jing; Koh, Tong-Wey

doi:10.1016/j.celrep.2022.111852

Cited by 15 publications

(16 citation statements)

References 160 publications

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“…Similarly, increasing NMNAT2 expression broadly provides neuroprotection across mouse models of tauopathy [21,146], familiar AD [147], and glaucoma [148]. Coincidently, upregulating glycolysis exerts neuroprotective effect in PD synucleinopathy and ALS models [149,150]. Our study highlights a novel role of NMNAT2 in supporting glycolysis in long-range projecting axons of cortical glutamatergic neurons.…”

Section: Discussionmentioning

confidence: 69%

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport

Yang

Niou

Enriquez

et al. 2023

Preprint

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Background Bioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimer’s, Parkinson's, and Huntington’s disease. Here we addressed whether NMNAT2 is required for axonal health of cortical glutamatergic neurons, whose long-projecting axons are often vulnerable in neurodegenerative conditions. We also tested if NMNAT2 maintains axonal health by ensuring axonal ATP levels for axonal transport, critical for axonal function. Methods We generated mouse and cultured neuron models to determine the impact of NMNAT2 loss from cortical glutamatergic neurons on axonal transport, energetic metabolism, and morphological integrity. In addition, we determined if exogenous NAD supplementation or inhibiting a NAD hydrolase, sterile alpha and TIR motif-containing protein 1 (SARM1), prevented axonal deficits caused by NMNAT2 loss. This study used a combination of genetics, molecular biology, immunohistochemistry, biochemistry, fluorescent time-lapse imaging, live imaging with optical sensors, and anti-sense oligos. Results We provide in vivo evidence that NMNAT2 in glutamatergic neurons is required for axonal survival. Using in vivo and in vitro studies, we demonstrate that NMNAT2 maintains the NAD-redox potential to provide “on-board” ATP via glycolysis to vesicular cargos in distal axons. Exogenous NAD+ supplementation to NMNAT2 KO neurons restores glycolysis and resumes fast axonal transport. Finally, we demonstrate both in vitro and in vivo that reducing the activity of SARM1, an NAD degradation enzyme, can reduce axonal transport deficits and suppress axon degeneration in NMNAT2 KO neurons. Conclusion NMNAT2 ensures axonal health by maintaining NAD redox potential in distal axons to ensure efficient vesicular glycolysis required for fast axonal transport.

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Section: Discussionmentioning

confidence: 69%

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport

Yang

Niou

Enriquez

et al. 2023

Preprint

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“…These lines targeted the Drosophila orthologues of the selected human genes, which were identi ed using the DIOPT Ortholog Finder 40 . Finally, we crossed 107 lines targeting 92 genes with the Drosophila synucleinopathy model to examine whether they can in uence α-syn-induced vacuole formation in the lamina 41 (Supplementary Data 1).…”

Section: Drosophila Screen Identi Es Mino Rnai As a Suppressor Of α-S...mentioning

confidence: 99%

Identification of Glycerol 3-phosphate acyltransferase as a potent modifier of α-Synuclein-induced toxicity

Lim,

Ren,

Lim

et al. 2024

Preprint

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Although multiple cellular pathways have been implicated in a-Synuclein (a-syn)-associated Parkinson’s disease (PD), the role of lipid metabolism remains elusive. Using the Drosophila system as a genetic screening tool, we identified mino, which encodes the mitochondrial isoform of the lipid synthesis enzyme glycerol 3-phosphate acyltransferase (GPAT), as a potent modifier of a-syn. Silencing the expression of mino significantly suppresses a-syn-induced PD phenotypes in Drosophila, including dopaminergic neuronal loss and locomotion defects as well as circadian rhythm-related activities, whereas mino overexpression yields opposite effects. Mechanistically, we found that mino modulates the levels of mitochondrial reactive oxygen speciesand lipid peroxidation. Importantly, treatment of a-syn-expressing flies with FSG67, a GPAT inhibitor, reproduces the benefits of mino knockdown. FSG67 also inhibited a-syn aggregation and lipid peroxidation in mouse primary neurons transfected with a-syn preformed fibrils. Our study elucidates an important factor contributing to a-syn toxicity and offers a novel therapeutic direction for PD.

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“…In other cases, the disease is associated with disease-causing variants with incomplete penetrance, such as those in the LRRK2 and GBA genes ( Healy et al, 2008 ; Sidransky et al, 2009 ; Milenkovic et al, 2022 ; Rocha et al, 2022 ). New insights have also been driven by the discovery of genetic modifiers and oligogenic etiology of PD ( Lubbe et al, 2016 ; Robak et al, 2017 ; Rousseaux et al, 2018 ; Bandres-Ciga et al, 2020 ; Blauwendraat et al, 2020b ; Iwaki et al, 2020 ; Ren et al, 2022 ; Straniero et al, 2022 ).…”

Section: Parkinson’s Disease and Parkinsonismmentioning

confidence: 99%

Sphingolipids in neurodegenerative diseases

Pan

Dutta

et al. 2023

Front. Neurosci.

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Neurodegenerative Diseases (NDDs) are a group of disorders that cause progressive deficits of neuronal function. Recent evidence argues that sphingolipid metabolism is affected in a surprisingly broad set of NDDs. These include some lysosomal storage diseases (LSDs), hereditary sensory and autonomous neuropathy (HSAN), hereditary spastic paraplegia (HSP), infantile neuroaxonal dystrophy (INAD), Friedreich’s ataxia (FRDA), as well as some forms of amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD). Many of these diseases have been modeled in Drosophila melanogaster and are associated with elevated levels of ceramides. Similar changes have also been reported in vertebrate cells and mouse models. Here, we summarize studies using fly models and/or patient samples which demonstrate the nature of the defects in sphingolipid metabolism, the organelles that are implicated, the cell types that are initially affected, and potential therapeutics for these diseases.

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MED13 and glycolysis are conserved modifiers of α-synuclein-associated neurodegeneration

Cited by 15 publications

References 160 publications

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport

NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport

Identification of Glycerol 3-phosphate acyltransferase as a potent modifier of α-Synuclein-induced toxicity

Sphingolipids in neurodegenerative diseases

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