Protein Arginine Methyltransferase 1 Ablation in Motor Neurons Causes Mitochondrial Dysfunction Leading to Age-related Motor Neuron Degeneration with Muscle Loss

So, Hyun-Kyung; Kim, Hyebeen; Lee, Jinwoo; You, Cheol‐Hwan; Yun, Chae-Eun; Jeong, Hyeon‐Ju; Jin, Eun‐Ju; Jo, Yunju; Ryu, Dongryeol; Bae, Gyu‐Un; Kang, Jong‐Sun

doi:10.34133/research.0158

Cited by 10 publications

(3 citation statements)

References 40 publications

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“…Thus, PRMT1 upregulation in sALS and its possible consequences on the epigenetic landscape and downstream transcriptome may occur rather late in the cascade of cellular events that mark neurodegeneration and could, therefore, represent a compensatory mechanism. In agreement with a neuroprotective role of PRMT1 upregulation on sALS, conditional PRMT1 knockout in motoneurons was recently demonstrated to trigger neurodegeneration and dismantlement of the neuromuscular junction leading to muscle wasting and lethality [ 107 ]. Importantly, this paradigm mimics PRMT1 loss of nuclear function, which accompanies FUS mutations.…”

Section: Histone Methylationmentioning

confidence: 80%

From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis

Hernan-Godoy,

Rouaux

2024

Cells

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The etiology of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) is complex and considered multifactorial. The majority of ALS cases are sporadic, but familial cases also exist. Estimates of heritability range from 8% to 61%, indicating that additional factors beyond genetics likely contribute to ALS. Numerous environmental factors are considered, which may add up and synergize throughout an individual’s lifetime building its unique exposome. One level of integration between genetic and environmental factors is epigenetics, which results in alterations in gene expression without modification of the genome sequence. Methylation reactions, targeting DNA or histones, represent a large proportion of epigenetic regulations and strongly depend on the availability of methyl donors provided by the ubiquitous one-carbon (1C) metabolism. Thus, understanding the interplay between exposome, 1C metabolism, and epigenetic modifications will likely contribute to elucidating the mechanisms underlying altered gene expression related to ALS and to developing targeted therapeutic interventions. Here, we review evidence for 1C metabolism alterations and epigenetic methylation dysregulations in ALS, with a focus on the impairments reported in neural tissues, and discuss these environmentally driven mechanisms as the consequences of cumulative exposome or late environmental hits, but also as the possible result of early developmental defects.

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Section: Histone Methylationmentioning

confidence: 80%

From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis

Hernan-Godoy,

Rouaux

2024

Cells

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“…Oxidative stress and low-grade inflammation are widely accepted factors in aging-related diseases [25]. AS was considered a chronic degenerative disease closely related to aging [26,27].…”

Section: Discussionmentioning

confidence: 99%

PinX1 Alleviates Atherosclerosis by Inhibiting MMP-9 Expression and p66shc-Mediated Oxidative Stress

Yang¹,

Zhang²,

Hong-xia³

et al. 2023

Preprint

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Atherosclerosis (AS) is an age-related disease. Mitochondria and telomere links have been considered to play important roles in AS. PinX1 is a potent and highly conserved endogenous telomerase inhibitor. However, the role of pinX1 in AS and its role in oxidative stress have not been reported. In order to investigate the role of pinX1 in AS, we established a classical AS mice model in the present work and increased pinX1 protein expression using pinX1 overexpression adeno-virus by tail vein injection. Then, red-oil O and HE staining were employed to evaluate the severity of AS. Serum lipid profile and oxidative stress were also detected by using its specific chemical testing kit. The results indicated that high-fat diet (HFD) markedly decreased pinX1 and increased p66shc protein expression, whereas overexpression of pinX1 protein expression in mice produced the opposite results. In addition, pinX1 significantly minimized plaque area and alleviated the abnormal serum lipid profile. By using Western blot and Biochemical assay kits, overexpression of pinX1 decreased p66shc and MMP-9 protein expression and reduced oxidative stress. This study showed pinX1 can inhibit p66shc, MMP-9, and related oxidative stress, pinX1 may be considered as a new candidate target for the treatment of AS.

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“…The deficiency of the respiratory chain results in increased electron leakage and reduced adenosine 5′-triphosphate (ATP) generation. Combined with impaired mitochondrial integrity, biogenesis, and mitochondria clearance, these factors have a profound influence on the aging process [ 8 , 19 ]. Interestingly, many mitochondrial proteins are predicted as targets of glycosylation [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Fut2 Deficiency Promotes Intestinal Stem Cell Aging by Damaging Mitochondrial Functions via Down-Regulating α1,2-Fucosylation of Asah2 and Npc1

Duan,

Wang,

et al. 2024

Research

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Fut2-mediated α1,2-fucosylation is important for gut homeostasis, including the intestinal stem cell (ISC). The stemness of ISC declines with age, and aging-associated ISC dysfunction is closely related to many age-related intestinal diseases. We previously found intestinal epithelial dysfunction in some aged Fut2 knockout mice. However, how Fut2-mediated α1,2-fucosylation affects ISC aging is still unknown. On this basis, the herein study aims to investigate the role of Fut2-mediated α1,2-fucosylation in ISC aging. Aging models in ISC-specific Fut2 knockout mice were established. ISCs were isolated for proteomics and N-glycoproteomics analysis. ISC functions and mitochondrial functions were examined in mice and organoids. Ulex europaeus agglutinin I chromatography and site-directed mutagenesis were used to validate the key target fucosylated proteins of Fut2. As a result, Fut2 knockout impaired ISC stemness and promoted aging marker expression in aged mice. Proteomics analysis indicated mitochondrial dysfunction in Fut2 knockout ISC. More injured mitochondria, elevated levels of reactive oxygen species, and decreased levels of adenosine 5′-triphosphate (ATP) in Fut2 knockout ISC were found. Moreover, respiratory chain complex impairment and mitophagy dysfunction in Fut2 knockout ISC were further noted. Finally, Fut2 was demonstrated to regulate mitochondrial functions mainly by regulating the α1,2-fucosylation of N -acyl sphingosine amidohydrolase 2 (Asah2) and Niemann–Pick type C intracellular cholesterol transporter 1 (Npc1). In conclusion, this study demonstrated the substantial role of Fut2 in regulating ISC functions during aging by affecting mitochondrial function. These findings provide novel insights into the molecular mechanisms of ISC aging and therapeutic strategies for age-related intestinal diseases.

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Protein Arginine Methyltransferase 1 Ablation in Motor Neurons Causes Mitochondrial Dysfunction Leading to Age-related Motor Neuron Degeneration with Muscle Loss

Cited by 10 publications

References 40 publications

From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis

From Environment to Gene Expression: Epigenetic Methylations and One-Carbon Metabolism in Amyotrophic Lateral Sclerosis

PinX1 Alleviates Atherosclerosis by Inhibiting MMP-9 Expression and p66shc-Mediated Oxidative Stress

Fut2 Deficiency Promotes Intestinal Stem Cell Aging by Damaging Mitochondrial Functions via Down-Regulating α1,2-Fucosylation of Asah2 and Npc1

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