α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism

Ghosh, Soumitra; Won, Seok Joon; Wang, Jiejie; Fong, Rebecca; Butler, Nicholas J.M.; Moss, Arianna; Wong, Candance; Pan, Jiehong; Sanchez, Jennifer; Huynh, Annie; Wu, Long; Manfredsson, Fredric P.; Swanson, Raymond A.

doi:10.1016/j.pneurobio.2021.102070

Cited by 25 publications

(24 citation statements)

References 64 publications

(21 reference statements)

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“…Regarding the role of NAC in PD, a recent investigation showed that oxidative stressinducing conditions and toxic α-synuclein conditions resulted in c-Abl activation. NAC administration reversed this effect, accompanied by improvement in dopaminergic neuronal death and motor amelioration in a murine PD model [ 420 ]. Accordingly, recently a notable gain in DAT binding has been reported in the caudate and putamen of patients with idiopathic PD supplemented with NAC therapy.…”

Section: Modulation Of Cysteinet By N -Acetyl-cyst...mentioning

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: Modulation Of Cysteinet By N -Acetyl-cyst...mentioning

confidence: 99%

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

Martínez-Banaclocha

2022

Antioxidants

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“…Cell-based therapy is a sustainable option that can reduce neurological inflammation in PD [ 61 ]. Spheramine (BAY86-5280) is a human retinal cultured epithelial pigment that produces levodopa [ 62 ]. In a phase II trial, 35 PD patients were transplanted spheramine (325,000 cells/side) into the post-commissural putamen by micro-carrier in 36 PD patients who underwent sham surgery ( Table 2 ) (NCT00206687).…”

Section: Pd Therapeutic Strategies In Clinical Trialsmentioning

confidence: 99%

“…In a phase II trial, 35 PD patients were transplanted spheramine (325,000 cells/side) into the post-commissural putamen by micro-carrier in 36 PD patients who underwent sham surgery ( Table 2 ) (NCT00206687). The result showed spheramine did not have significant anti-parkinsonism effects (change in mean motor scores did not differ significantly between groups) [ 62 ]. In this trial, 2 and 7 patients died in the sham surgery and spheramine transplantation group, respectively [ 62 ].…”

Section: Pd Therapeutic Strategies In Clinical Trialsmentioning

confidence: 99%

“…The result showed spheramine did not have significant anti-parkinsonism effects (change in mean motor scores did not differ significantly between groups) [ 62 ]. In this trial, 2 and 7 patients died in the sham surgery and spheramine transplantation group, respectively [ 62 ]. Porcine choroid plexus produces several neurotrophins and can be safely delivered to the striatum in an encapsulated formulation to protect them from immune attack [ 63 ].…”

Section: Pd Therapeutic Strategies In Clinical Trialsmentioning

confidence: 99%

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Current Therapies in Clinical Trials of Parkinson’s Disease: A 2021 Update

Prasad

Hung

2021

Pharmaceuticals

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder that currently has no cure, but treatments are available to improve PD symptoms and maintain quality of life. In 2020, about 10 million people worldwide were living with PD. In 1970, the United States Food and Drug Administration approved the drug levodopa as a dopamine replacement to manage PD motor symptoms; levodopa-carbidopa combination became commercialized in 1975. After over 50 years of use, levodopa is still the gold standard for PD treatment. Unfortunately, levodopa therapy-induced dyskinesia and OFF symptoms remain unresolved. Therefore, we urgently need to analyze each current clinical trial’s status and therapeutic strategy to discover new therapeutic approaches for PD treatment. We surveyed 293 registered clinical trials on ClinicalTrials.gov from 2008 to 16 June 2021. After excluded levodopa/carbidopa derivative add-on therapies, we identified 47 trials as PD treatment drugs or therapies. Among them, 19 trials are in phase I (41%), 25 trials are in phase II (53%), and 3 trials are in phase III (6%). The three phase-III trials use embryonic dopamine cell implant, 5-HT1A receptor agonist (sarizotan), and adenosine A2A receptor antagonist (caffeine). The therapeutic strategy of each trial shows 29, 5, 1, 5, 5, and 2 trials use small molecules, monoclonal antibodies, plasma therapy, cell therapy, gene therapy, and herbal extract, respectively. Additionally, we discuss the most potent drug or therapy among these trials. By systematically updating the current trial status and analyzing the therapeutic strategies, we hope this review can provide new ideas and insights for PD therapy development.

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“…Nilotinib, an oral cellular Abelson tyrosine kinase (c-Abl) inhibitor, was approved for the treatment of chronic myeloid leukemia (CML) at dosages of 300 mg twice daily by the U.S FDA in 2007 (Deremer et al, 2008 ; Sacha and Saglio, 2019 ). Some studies found increased activation of c-Abl in PD models and in brain tissues of PD patients (Imam et al, 2011 ; Brahmachari et al, 2016 , 2019 ; Karim et al, 2020 ; Ghosh et al, 2021 ). suggesting that c-Abl might be associated with PD progression and that its inhibitor nillotinib might have a potential benefit in treating PD.…”

Section: Introductionmentioning

confidence: 99%

Nilotinib in Parkinson's disease: A systematic review and meta-analysis

Xie

Yuan

Kou

et al. 2022

Front. Aging Neurosci.

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BackgroundNilotinib, which inhibits cellular Abelson tyrosine kinase, may be an effective treatment for patients with Parkinson's disease (PD). The purpose of this study is to evaluate the outcomes of different doses of nilotinib in patients with PD.MethodsWe searched PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Clinical Trials from inception to 7 March 2022 to identify all randomized controlled trials (RCTs) of nilotinib reporting outcomes of interest in patients with PD. Outcomes included tolerability, efficacy, safety, and CSF biomarker levels. Review manager 5.4 software was used to analyze all data.ResultsThree RCTs with a total of 163 patients were included. No significant difference was found between 150 mg nilotinib or 300 mg nilotinib and placebo in terms of tolerability, adverse events, or HVA levels. 300 mg nilotinib showed significantly higher Movement Disorder Society Unified Parkinson's Disease Rating Scale III (MDS-UPDRS III) scores [SMD = 0.52, 95%CI = (0.12, 0.92), P = 0.01] and 3,4-dihydroxyphenylacetic acid (DOPAC) levels [SMD = 0.52, 95%CI = (0.12, 0.92), P = 0.01], and lower α-synuclein levels [SMD = −2.16, 95%CI = (−3.38, −1.84), P < 0.00001] compared with placebo. And compared with 150 mg nilotinib, 300 mg nilotinib showed significantly lower α-synuclein levels [SMD = −1.16, 95%CI = (−1.70, −0.61), P < 0.0001].ConclusionsAlthough our study demonstrated favorable tolerability and safety of different doses of nilotinib, and improvement in part of CSF biomarker levels of 300 mg nilotinib, the poor efficacy on motor outcomes indicated that nilotinib had no advantages in the clinic.

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α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism

Cited by 25 publications

References 64 publications

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

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

Current Therapies in Clinical Trials of Parkinson’s Disease: A 2021 Update

Nilotinib in Parkinson's disease: A systematic review and meta-analysis

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