N‐homocysteinylation of α‐synuclein promotes its aggregation and neurotoxicity

Zhou, Lingyan; Guo, Tao; Meng, Lanxia; Zhang, Xingyu; Tian, Ye; Dai, Lingyun; Niu, Xuan; Li, Yiming; Liu, Congcong; Chen, Guiqin; Liu, Chaoyang; Ke, Wei; Zhang, Zhaohui; Bao, Anyu; Zhang, Zhentao

doi:10.1111/acel.13745

Cited by 13 publications

(14 citation statements)

References 45 publications

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“…Aging is the most important risk factor for PD. Interestingly, we found that the levels of both Hcy and HTL in the mouse brain increased in an age‐related manner (Zhou et al., 2022 ). Consistently, IHC and Western blot analyses revealed that the level of DJ‐1 K182Hcy increased during aging in the brains of TgA53T mice (Figure 3e–h ).…”

Section: Resultsmentioning

confidence: 94%

“…Protein N‐hcy can be labeled with azide probes (Chen et al., 2019 ; Zhou et al., 2022 ). To investigate whether DJ‐1 undergoes N‐hcy, we transfected HEK293 cells with plasmids encoding hemagglutinin (HA)‐tagged DJ‐1, and then exposed the cells to 0.1 mM HTL for 24 h. The cell lysates were subjected to chemical reaction with a biotin‐azide probe.…”

Section: Resultsmentioning

confidence: 99%

“…Hcy is a byproduct of the methionine metabolism pathway. Administration of L‐methionine (Met) increases the levels of Hcy and HTL in the mouse brain (Zhou et al., 2022 ). Thus, we further tested the effect of Met administration on mice injected with MPTP, one of the most widely used neurotoxins for inducing PD‐like dopaminergic neurodegeneration in mice.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, protein N‐hcy in early life persists during aging (Bossenmeyer‐Pourié et al., 2019 ). Likewise, the N‐hcy of α‐syn exacerbates α‐syn aggregation, neurotoxicity, and dopaminergic neuronal degeneration (Zhou et al., 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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N‐homocysteinylation of DJ‐1 promotes neurodegeneration in Parkinson's disease

Guo,

Zhou,

Xiong

et al. 2024

Aging Cell

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DJ‐1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ‐1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ‐1 on the lysine 182 (K182) residue in an age‐dependent manner. The N‐homocysteinylation (N‐hcy) of DJ‐1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N‐hcy of DJ‐1 restores its protective effect. These results indicate that the N‐hcy of DJ‐1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N‐hcy of DJ‐1 may exert neuroprotective effect against PD.

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Section: Resultsmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

N‐homocysteinylation of DJ‐1 promotes neurodegeneration in Parkinson's disease

Guo,

Zhou,

Xiong

et al. 2024

Aging Cell

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“…Accumulation of Hcy-thiolactone is harmful because of its ability to modify protein lysine residues (6), which generates structurally- and functionally-impaired N -homocysteinylated ( N -Hcy)-proteins with proinflammatory, prothrombotic, and pro-amyloidogenic properties (7). Hcy-thiolactone and N -Hcy-proteins accumulate in mentally retarded CBS- and MTHFR-deficient patients (7) and are mechanistically linked to neurological diseases such as Alzheimer’s disease (AD) (8, 9), stroke (10), cognitive impairment (11), Parkinson’s disease (12), and neural tube defects (13, 14), as well as cardiovascular disease (15), cancer (16–18), and rheumatoid arthritis (19).…”

Section: Introductionmentioning

confidence: 99%

Depletion of bleomycin hydrolase (Blmh) downregulates histone demethylase Phf8, impairs mTOR signaling/autophagy, accelerates amyloid beta accumulation, and induces neurological deficits in mice

Witucki

Borowczyk

Suszyńska-Zajczyk

et al. 2023

Preprint

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Bleomycin hydrolase (BLMH), a homocysteine (Hcy)-thiolactone detoxifying enzyme, is attenuated in brains of Alzheimers disease patients. In mice, Blmh depletion causes astrogliosis and behavioral changes. Depletion of histone demethylase PHF8, which controls mTOR signaling by demethylating H4K20me1, causes neuropathy in humans and mice. Here we examined how Blmh depletion affects the Phf8/H4K20me1/mTOR signaling/autophagy pathway and amyloid beta (Ab) accumulation and cognitive/neuromotor performance in mice. We found that Phf8 was significantly downregulated in brains of Blmh-/- mice vs. Blmh+/+ sibling controls. H4K20me1, mTOR, phospho-mTOR, and App were upregulated while autophagy markers Bcln1, Atg5, and Atg7 were downregulated in Blmh-/- brains. Blmh depletion caused similar biochemical changes and significantly elevated Ab in Blmh-/-5xFAD vs. Blmh+/+5xFAD brains. Behavioral testing identified cognitive/neuromotor deficits in Blmh-/- and Blmh-/-5xFAD mice. In Blmh-depleted N2a-APPswe cells, Phf8 was downregulated, while APP, total H4K20me1, and H4K20me1-mTOR promoter binding were elevated. This led to mTOR upregulation, autophagy downregulation, and significantly increased APP and Ab levels. Phf8 depletion or treatments with Hcy-thiolactone or N-Hcy-protein, metabolites that are elevated in Blmh-depleted mice, induced similar biochemical changes in N2a-APPswe cells, akin to those in induced by Blmh depletion. Taken together, our findings indicate that Blmh interacts with APP and the Phf8/H4K20me1/mTOR/autophagy pathway and show that disruption of these interactions lead to Ab accumulation and cognitive and neuromotor deficits.

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Parkinson's disease and vitamins: a focus on vitamin B12

Rekik,

Santoro,

Poplawska-Domaszewicz

et al. 2024

J Neural Transm

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Parkinson’s disease (PD) has been linked to a vast array of vitamins among which vitamin B12 (Vit B12) is the most relevant and often investigated specially in the context of intrajejunal levodopa infusion therapy. Vit B12 deficiency, itself, has been reported to cause acute parkinsonism. Nevertheless, concrete mechanisms through which B12 deficiency interacts with PD in terms of pathophysiology, clinical manifestation and progression remains unclear. Recent studies have suggested that Vit B12 deficiency along with the induced hyperhomocysteinemia are correlated with specific PD phenotypes characterized with early postural instability and falls and more rapid motor progression, cognitive impairment, visual hallucinations and autonomic dysfunction. Specific clinical features such as polyneuropathy have also been linked to Vit B12 deficiency specifically in context of intrajejunal levodopa therapy. In this review, we explore the link between Vit B12 and PD in terms of physiopathology regarding dysfunctional neural pathways, neuropathological processes as well as reviewing the major clinical traits of Vit B12 deficiency in PD and Levodopa-mediated neuropathy. Finally, we provide an overview of the therapeutic effect of Vit B12 supplementation in PD and posit a practical guideline for Vit B12 testing and supplementation.

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N‐homocysteinylation of α‐synuclein promotes its aggregation and neurotoxicity

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 13 publications

References 45 publications

N‐homocysteinylation of DJ‐1 promotes neurodegeneration in Parkinson's disease

N‐homocysteinylation of DJ‐1 promotes neurodegeneration in Parkinson's disease

Depletion of bleomycin hydrolase (Blmh) downregulates histone demethylase Phf8, impairs mTOR signaling/autophagy, accelerates amyloid beta accumulation, and induces neurological deficits in mice

Parkinson's disease and vitamins: a focus on vitamin B12

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