Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction

Jeon, Yu-Mi; Kwon, Younghwi; Lee, Shinrye; Kim, Seyeon; Jo, Myungjin; Lee, Seongsoo; Kim, Sang Ryong; Kim, Ki‐Young

doi:10.3390/antiox11010082

Cited by 17 publications

(8 citation statements)

References 87 publications

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“…[13][14][15] Similarly, overexpression of ALS-associated TDP-43 variants or even the wild-type protein exerts deleterious effects across species, including motor deficits, shortened lifespan, and MN loss in animal models, [16][17][18][19][20] and cytotoxicity and various cellular dysfunctions in human immortalized neuron-like cells. [21][22][23] Given the potential confounding effects of overexpression strategies, discerning the pathological contributions of TARDBP mutations has been challenging. Progress in induced pluripotent stem cell (iPSC) technology now offer an unprecedented opportunity to study the impact of disease-associated mutations in human disease-relevant cell types.…”

Section: Introductionmentioning

confidence: 99%

Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons

Lépine

Nauleau-Javaudin

Deneault

et al. 2023

Preprint

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Cytoplasmic mislocalization and aggregation of the RNA-binding protein TDP-43 is a pathological hallmark of the motor neuron (MN) disease amyotrophic lateral sclerosis (ALS). Furthermore, while mutations in the TARDBP gene (encoding TDP-43) have been associated with ALS, the pathogenic consequences of these mutations remain poorly understood. Using CRISPR/Cas9, we engineered two homozygous knock-in iPSC lines carrying mutations in TARDBP encoding TDP-43A382Tand TDP-43G348C, two common yet understudied ALS TDP-43 variants. MNs differentiated from knock-in iPSCs had normal viability and displayed no significant changes in TDP-43 subcellular localization, phosphorylation, solubility, or aggregation compared with isogenic control MNs. However, our results highlight synaptic impairments in both TDP-43A382Tand TDP-43G348CMN cultures, as reflected in synapse abnormalities and alterations in spontaneous neuronal activity. Collectively, our findings argue that MN dysfunction precedes the occurrence of TDP-43 pathology and neurodegeneration in ALS, and further implicates synaptic and excitability defects in the pathobiology of this disease.

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Section: Introductionmentioning

confidence: 99%

Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons

Lépine

Nauleau-Javaudin

Deneault

et al. 2023

Preprint

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“…Vitamin B12 therefore represents a potential micronutrient to compensate reduced plasmalogen levels, which are commonly seen in brains affected by AD. Moreover, a recent study also reported that vitamin B12 reduces TDP-43 (TAR DNA-binding protein 43) toxicity in SH-SY5Y cells by reducing oxidative stress and mitochondrial dysfunction [ 134 ]. Cytoplasmic aggregation of TDP-43 represents a pathological hallmark of many neurodegenerative diseases, including AD, amyotrophic lateral sclerosis (ALS), frontotemporal dementia, and limbic predominant age-related TDP-43 encephalopathy, indicating that vitamin B12 is a possibly beneficial therapeutical micronutrient for several neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Vitamin B12 Attenuates Changes in Phospholipid Levels Related to Oxidative Stress in SH-SY5Y Cells

Theiss

Griebsch

Lauer

et al. 2022

Cells

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Oxidative stress is closely linked to Alzheimer’s disease (AD), and is detected peripherally as well as in AD-vulnerable brain regions. Oxidative stress results from an imbalance between the generation and degradation of reactive oxidative species (ROS), leading to the oxidation of proteins, nucleic acids, and lipids. Extensive lipid changes have been found in post mortem AD brain tissue; these changes include the levels of total phospholipids, sphingomyelin, and ceramide, as well as plasmalogens, which are highly susceptible to oxidation because of their vinyl ether bond at the sn-1 position of the glycerol-backbone. Several lines of evidence indicate that a deficiency in the neurotropic vitamin B12 is linked with AD. In the present study, treatment of the neuroblastoma cell line SH-SY5Y with vitamin B12 resulted in elevated levels of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and plasmalogens. Vitamin B12 also protected plasmalogens from hydrogen peroxide (H2O2)-induced oxidative stress due to an elevated expression of the ROS-degrading enzymes superoxide-dismutase (SOD) and catalase (CAT). Furthermore, vitamin B12 elevates plasmalogen synthesis by increasing the expression of alkylglycerone phosphate synthase (AGPS) and choline phosphotransferase 1 (CHPT1) in SH-SY5Y cells exposed to H2O2-induced oxidative stress.

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“…Protein intake is closely related to vitamin D and B12 levels [ 45 ]. Insufficient amounts of these vitamins can lead to higher levels of oxidative stress [ 46 , 47 , 48 , 49 ], so this fact could be explained by the relationship between protein intake and 8-isoprostane levels.…”

Section: Discussionmentioning

confidence: 99%

Maternal Diet Quality and the Health Status of Newborns

Pavlikova

Ambroz

Hoňková

et al. 2022

Foods

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The maternal diet during pregnancy affects neonatal health status. The objective of this study was to assess the nutritional quality of the maternal diet, and its contamination by persistent organic pollutants (POPs), in pregnant women living in two areas of the Czech Republic with different levels of air pollution, and subsequently to assess the relationship of these two factors with birth weight and neonatal oxidative stress. To determine the level of oxidative stress, 8-isoprostane concentrations in umbilical cord plasma were measured. The overall nutritional quality of the maternal diet was not optimal. Of the nutritional factors, protein intake proved to be the most significant showing a positive relationship with birth weight, and a negative relationship with the oxidative stress of newborns. Dietary contamination by persistent organic pollutants was low and showed no statistically significant relationship with birth weight. Only one of the 67 analyzed POPs, namely the insecticide dichlorodiphenyltrichloroethane (DDT), showed a statistically significant positive relationship with the level of neonatal oxidative stress.

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Vitamin B12 Reduces TDP-43 Toxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction

Cited by 17 publications

References 87 publications

Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons

Homozygous ALS-linked mutations in TARDBP/TDP-43 lead to hypoactivity and synaptic abnormalities in human iPSC-derived motor neurons

Vitamin B12 Attenuates Changes in Phospholipid Levels Related to Oxidative Stress in SH-SY5Y Cells

Maternal Diet Quality and the Health Status of Newborns

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