Methylation of alpha-synuclein in a Sudanese cohort

Bakhit, Yousuf; Schmitt, Imke; Hamed, Ahlam A.; Ibrahim, Etedal Ahmed A.; Mohamed, Inaam N.; El-Sadig, Sarah Misbah; Elseed, Maha A.; Alebeed, Mohamed A.; Shaheen, Mutaz T.; Ibrahim, Mohamed O.; Elhassan, Ali A.; Eltom, Khalid; Ali, Hiba A.; Ibrahim, Yousuf A.; Almak, Murad E.; Abubaker, Rayan; Ahmed, Mohamed Anwer; Abugrain, Ahmed A.; Mohamedelrasheed, Salma; Omar, Mawia A.; Almahal, Mohamed A.; MohamedSharif, Abubaker A.; Tahir, Mohamed Y.; Malik, Sawazen; Eldirdiri, Hazim S.; Khidir, Reem J.; Mohamed, Malaz Tarig AbdAlla; Abdalla, A. A.; Omer, Farouk Yassen; Elsayed, Liena; Babikir, Haydar El Hadi; Bukhari, Elfateh Abd-Allah; Seidi, Osheik; Wüllner, Ullrich

doi:10.1016/j.parkreldis.2022.05.009

Cited by 7 publications

(5 citation statements)

References 19 publications

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“…The fact that α-Syn can be found in different forms (monomeric, oligomeric, aggregated or post translational modified) in accessible and peripheral tissues such as CSF, blood, saliva, tears, colon, esophagus and skin ( Tokuda et al, 2010 ; Devic et al, 2011 ; Foulds et al, 2011 , 2012 ; Mollenhauer et al, 2013 ; Abd-Elhadi et al, 2015 ; Koehler et al, 2015 ; Chung et al, 2016 ; Cariulo et al, 2019 ; Fenyi et al, 2019 ; Hamm-Alvarez et al, 2019 ; Vivacqua et al, 2019 ; Maass et al, 2020 ; Wang et al, 2020b ; Tanei et al, 2021 ; Bakhit et al, 2022 ), opened up the possibility to evaluate whether these different proteoforms may be useful for the diagnosis of PD and or other synucleinopathies ( Witt et al, 2009 ; Pouclet et al, 2012 ; Shannon et al, 2012 ; Donadio et al, 2014 , 2018 ; Sprenger et al, 2015 ; Zange et al, 2015 ; Stokholm et al, 2016 ; Vilas et al, 2016 ; Fereshtehnejad et al, 2017 ; Fayyad et al, 2019 ; Parnetti et al, 2019 ; Vivacqua et al, 2019 , 2023 ; Wang et al, 2020b ; Ganguly et al, 2021 ).…”

Section: α-Syn Post-translational Modifications As Possible Biomarker...mentioning

confidence: 99%

Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?

Brembati

Faustini

Longhena

et al. 2023

Front. Mol. Neurosci.

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Parkinson’s disease (PD) is the most common neurodegenerative disorder with motor symptoms. The neuropathological alterations characterizing the brain of patients with PD include the loss of dopaminergic neurons of the nigrostriatal system and the presence of Lewy bodies (LB), intraneuronal inclusions that are mainly composed of alpha-synuclein (α-Syn) fibrils. The accumulation of α-Syn in insoluble aggregates is a main neuropathological feature in PD and in other neurodegenerative diseases, including LB dementia (LBD) and multiple system atrophy (MSA), which are therefore defined as synucleinopathies. Compelling evidence supports that α-Syn post translational modifications (PTMs) such as phosphorylation, nitration, acetylation, O-GlcNAcylation, glycation, SUMOylation, ubiquitination and C-terminal cleavage, play important roles in the modulation α-Syn aggregation, solubility, turnover and membrane binding. In particular, PTMs can impact on α-Syn conformational state, thus supporting that their modulation can in turn affect α-Syn aggregation and its ability to seed further soluble α-Syn fibrillation. This review focuses on the importance of α-Syn PTMs in PD pathophysiology but also aims at highlighting their general relevance as possible biomarkers and, more importantly, as innovative therapeutic targets for synucleinopathies. In addition, we call attention to the multiple challenges that we still need to face to enable the development of novel therapeutic approaches modulating α-Syn PTMs.

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Section: α-Syn Post-translational Modifications As Possible Biomarker...mentioning

confidence: 99%

Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?

Brembati

Faustini

Longhena

et al. 2023

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…In a study of post-mortem brains, a marked reduction in SNCA methylation was observed in the substantia nigra, putamen, and cortex of PD patients [ 42 ]. Although PD-related alterations in methylation status in intron 1 is controversial [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ], the induction of robust hypermethylation of SNCA CpG island results in a reduction in SNCA expression, which may be exploited as a therapeutic approach to prevent pathogenic αS accumulation [ 52 ]. This intron 1 domain is also associated with histone modification, and another epigenetic modulator, H3K4me3 transcriptional active mark, was more prevalent in the substantia nigra of PD brains [ 53 ].…”

Section: Interaction Between αS and Epigenetic Factorsmentioning

confidence: 99%

“… Changes in methylation status of CpG islands located in SNCA intron 1. ( A ) The indexed number of CpG sites is based on the report by Jowaed et al [ 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. The numbering of CpG sites is not identical in each study and is, therefore, corrected and displayed accordingly.…”

Section: Figurementioning

confidence: 99%

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

Sugeno

Hasegawa

2023

IJMS

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Alpha-synuclein (αS) is a small, presynaptic neuronal protein encoded by the SNCA gene. Point mutations and gene multiplication of SNCA cause rare familial forms of Parkinson’s disease (PD). Misfolded αS is cytotoxic and is a component of Lewy bodies, which are a pathological hallmark of PD. Because SNCA multiplication is sufficient to cause full-blown PD, gene dosage likely has a strong impact on pathogenesis. In sporadic PD, increased SNCA expression resulting from a minor genetic background and various environmental factors may contribute to pathogenesis in a complementary manner. With respect to genetic background, several risk loci neighboring the SNCA gene have been identified, and epigenetic alterations, such as CpG methylation and regulatory histone marks, are considered important factors. These alterations synergistically upregulate αS expression and some post-translational modifications of αS facilitate its translocation to the nucleus. Nuclear αS interacts with DNA, histones, and their modifiers to alter epigenetic status; thereby, influencing the stability of neuronal function. Epigenetic changes do not affect the gene itself but can provide an appropriate transcriptional response for neuronal survival through DNA methylation or histone modifications. As a new approach, publicly available RNA sequencing datasets from human midbrain-like organoids may be used to compare transcriptional responses through epigenetic alterations. This informatic approach combined with the vast amount of transcriptomics data will lead to the discovery of novel pathways for the development of disease-modifying therapies for PD.

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“…Current research indicates that variants in the SNCA gene, exposure to pesticides, and physical activity impact the epigenome, particularly at the level of CpG methylation, so these factors are key contributors to PD risk [ 57 , 58 ]. On the other hand, of the fourteen analyzed CpGs of SNCA intron1 , CpGs 16–23 were hypomethylated in PD [ 59 ].…”

Section: Familial and Sporadic Forms Of Pd Epigenetic Aspectsmentioning

confidence: 99%

Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

Dolgacheva

Зинченко

Гончаров

2022

IJMS

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An increasing number of the population all around the world suffer from age-associated neurodegenerative diseases including Parkinson’s disease (PD). This disorder presents different signs of genetic, epigenetic and environmental origin, and molecular, cellular and intracellular dysfunction. At the molecular level, α-synuclein (αSyn) was identified as the principal molecule constituting the Lewy bodies (LB). The gut microbiota participates in the pathogenesis of PD and may contribute to the loss of dopaminergic neurons through mitochondrial dysfunction. The most important pathogenetic link is an imbalance of Ca2+ ions, which is associated with redox imbalance in the cells and increased generation of reactive oxygen species (ROS). In this review, genetic, epigenetic and environmental factors that cause these disorders and their cause-and-effect relationships are considered. As a constituent of environmental factors, the example of organophosphates (OPs) is also reviewed. The role of endothelial damage in the pathogenesis of PD is discussed, and a ‘triple hit hypothesis’ is proposed as a modification of Braak’s dual hit one. In the absence of effective therapies for neurodegenerative diseases, more and more evidence is emerging about the positive impact of nutritional structure and healthy lifestyle on the state of blood vessels and the risk of developing these diseases.

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Methylation of alpha-synuclein in a Sudanese cohort

Cited by 7 publications

References 19 publications

Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?

Alpha synuclein post translational modifications: potential targets for Parkinson’s disease therapy?

Unraveling the Complex Interplay between Alpha-Synuclein and Epigenetic Modification

Molecular and Cellular Interactions in Pathogenesis of Sporadic Parkinson Disease

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