N-Acetylcysteine prevents amyloid-β secretion in neurons derived from human pluripotent stem cells with trisomy 21

Toshikawa, Hiromitsu; Ikenaka, Akihiro; Li, Li; Nishinaka‐Arai, Yoko; Niwa, Akira; Ashida, Akira; Kazuki, Yasuhiro; Nakahata, Tatsutoshi; Tamai, Hiroshi; Russell, David W.; Saito, Megumu K.

doi:10.1038/s41598-021-96697-7

Cited by 4 publications

(4 citation statements)

References 52 publications

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“…Additionally, the role of oxidative damage and disulfide bond formation in tau [ 441 ] and other SCCPs are critical triggering mechanisms leading to neurodegenerative disorders and pathogenic progression factors. Therefore, NAC may offer an effective therapeutic strategy to decrease the generation and spread of pathological proteins [ 442 ].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

Martínez-Banaclocha

2022

Antioxidants

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In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased risk of neurodegenerative diseases to slow down their progression, poor prognosis, and decreasing quality of life. Accordingly, it is urgent to implement interventions addressing the psychosocial and biochemical disturbances we know are central in managing the evolution of these disorders. Genomic and proteomic studies have shown the high molecular intricacy in neurodegenerative diseases, involving a broad spectrum of cellular pathways underlying disease progression. Recent investigations indicate that the dysregulation of the sensitive-cysteine proteome may be a concurrent pathogenic mechanism contributing to the pathophysiology of major neurodegenerative diseases, opening new therapeutic opportunities. Considering the incidence and prevalence of these disorders and their already significant burden in Western societies, they will become a real pandemic in the following decades. Therefore, we propose large-scale investigations, in selected groups of people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment, to evaluate supplementation of the diet with low doses of N-acetyl-cysteine, a promising and well-tolerated therapeutic agent suitable for long-term use.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

Martínez-Banaclocha

2022

Antioxidants

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“…Directed differentiation of DS NPCs to mixed cortical neurons is associated with impaired maturation and synaptic deficits ( Weick et al, 2013 ; Hibaoui et al, 2014 ) ( Table 1 ). Further, elevated oxidative stress ( Weick et al, 2013 ; Dashinimaev et al, 2017 ; Sobol et al, 2019 ; Toshikawa et al, 2021 ), increased cell death, and pathological hallmarks of AD such as elevated amyloid-ß and hyperphosphorylated tau ( Shi et al, 2012a ; Dashinimaev et al, 2017 ; Toshikawa et al, 2021 ) have also been observed in DS iPSC-derived neurons ( Table 1 ). Transcription factor-driven ( NGN2 ) neuronal differentiation resulted in increased apoptosis of T21 neurons that was associated with dysregulated protein homeostasis and upregulation of endoplasmic reticulum stress pathway ( Hirata et al, 2020 ).…”

Section: Ipsc-derived Neuronsmentioning

confidence: 99%

From neurodevelopment to neurodegeneration: utilizing human stem cell models to gain insight into Down syndrome

Watson

Meharena

2023

Front. Genet.

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Down syndrome (DS), caused by triplication of chromosome 21, is the most frequent aneuploidy observed in the human population and represents the most common genetic form of intellectual disability and early-onset Alzheimer’s disease (AD). Individuals with DS exhibit a wide spectrum of clinical presentation, with a number of organs implicated including the neurological, immune, musculoskeletal, cardiac, and gastrointestinal systems. Decades of DS research have illuminated our understanding of the disorder, however many of the features that limit quality of life and independence of individuals with DS, including intellectual disability and early-onset dementia, remain poorly understood. This lack of knowledge of the cellular and molecular mechanisms leading to neurological features of DS has caused significant roadblocks in developing effective therapeutic strategies to improve quality of life for individuals with DS. Recent technological advances in human stem cell culture methods, genome editing approaches, and single-cell transcriptomics have provided paradigm-shifting insights into complex neurological diseases such as DS. Here, we review novel neurological disease modeling approaches, how they have been used to study DS, and what questions might be addressed in the future using these innovative tools.

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“…Oxidative injury and disulfide bridges in tau and other SCCPs are crucial pathogenic factors [266], and APOE4 and tau implication in PD dementia has lately been identified [267]. Hence, targeting the cysteine redox proteome is a potential preventive strategy against PD initiation and evolution [268].…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Targeting the Cysteine Redox Proteome in Parkinson’s Disease: The Role of Glutathione Precursors and Beyond

Martínez-Banaclocha

2023

Antioxidants

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Encouraging recent data on the molecular pathways underlying aging have identified variants and expansions of genes associated with DNA replication and repair, telomere and stem cell maintenance, regulation of the redox microenvironment, and intercellular communication. In addition, cell rejuvenation requires silencing some transcription factors and the activation of pluripotency, indicating that hidden molecular networks must integrate and synchronize all these cellular mechanisms. Therefore, in addition to gene sequence expansions and variations associated with senescence, the optimization of transcriptional regulation and protein crosstalk is essential. The protein cysteinome is crucial in cellular regulation and plays unexpected roles in the aging of complex organisms, which show cumulative somatic mutations, telomere attrition, epigenetic modifications, and oxidative dysregulation, culminating in cellular senescence. The cysteine thiol groups are highly redox-active, allowing high functional versatility as structural disulfides, redox-active disulfides, active-site nucleophiles, proton donors, and metal ligands to participate in multiple regulatory sites in proteins. Also, antioxidant systems control diverse cellular functions, including the transcription machinery, which partially depends on the catalytically active cysteines that can reduce disulfide bonds in numerous target proteins, driving their biological integration. Since we have previously proposed a fundamental role of cysteine-mediated redox deregulation in neurodegeneration, we suggest that cellular rejuvenation of the cysteine redox proteome using GSH precursors, like N-acetyl-cysteine, is an underestimated multitarget therapeutic approach that would be particularly beneficial in Parkinson’s disease.

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N-Acetylcysteine prevents amyloid-β secretion in neurons derived from human pluripotent stem cells with trisomy 21

Cited by 4 publications

References 52 publications

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

From neurodevelopment to neurodegeneration: utilizing human stem cell models to gain insight into Down syndrome

Targeting the Cysteine Redox Proteome in Parkinson’s Disease: The Role of Glutathione Precursors and Beyond

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