Nicotine slows down oligomerisation of α-synuclein and ameliorates cytotoxicity in a yeast model of Parkinson's disease

Kardani, Jay; Sethi, R.; Roy, Ipsita

doi:10.1016/j.bbadis.2017.02.002

Cited by 42 publications

(36 citation statements)

References 56 publications

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“…SNCG expression is normally restricted to the brain and peripheral neuronal tissues [14], and its aberrant expression in tissues other than those of the neuronal system is highly associated with human malignancy. Previous studies have reported that nicotine acting on brain nAChRs may affect SNCA aggregation, resulting in neuroprotection [15][16][17]. Recently, we reported that SNCG is abnormally expressed in OSCC and that its expression is strongly correlated with disease progression [2].…”

Section: Introductionmentioning

confidence: 93%

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy

Hsu

Tsai

et al. 2020

Cancer Cell Int

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Background: The mechanisms of neuronal protein γ-synuclein (SNCG) in the malignancy of oral squamous cell carcinoma (OSCC) are not clear. This study tested the hypothesis that SNCG is involved in nicotine-induced malignant behaviors of OSCC. The effect of nicotine on SNCG expression and epithelial-to-mesenchymal transition (EMT) markers were examined. Methods: Short hairpin RNA (shRNA) and an antagonist specific for α7-nicotine acetylcholine receptors (α7-nAChRs) were used to examine the role of α7-nAChRs in mediating the effects of nicotine. Knockdown of SNCG in nicotinetreated cells was performed to investigate the role of SNCG in cancer malignancy. The in vivo effect of nicotine was examined using a nude mouse xenotransplantation model. Results: Nicotine increased SNCG expression in a time-and dose-dependent manner. Nicotine treatment also increased E-cadherin and ZO-1 and decreased fibronectin and vimentin expression. After specific knockdown of α7-nAChRs and inhibition of the PI3/AKT signal, the effect of nicotine on SNCG expression was attenuated. Silencing of SNCG abolished nicotine-induced invasion and migration of OSCC cells. The xenotransplantation model revealed that nicotine augmented tumor growth and SNCG expression. Conclusion: Nicotine upregulated SNCG expression by activating the α7-nAChRs/PI3/AKT signaling that are participated in nicotine-induced oral cancer malignancy.

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Section: Introductionmentioning

confidence: 93%

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy

Hsu

Tsai

et al. 2020

Cancer Cell Int

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“…Among the compounds with a possible clinical application, dopaminergic agonists were found to directly affect aggregation in a Drosophila melanogaster model of α‐syn accumulation . In line with epidemiological evidence supporting that cigarette smoking lowers the risk of PD, nicotine, the main tobacco component has been found to display antifibrillogenic properties by inhibiting de novo α‐syn oligomerization and fibril formation and destabilizing preformed α‐syn fibrils in yeast . Other molecules, including psychostimulants with amphetamine‐like structure, as cocaine or methylphenidate, have been found to interact with α‐syn with differential modalities, involving either the sole N‐terminal portion or a contemporaneous N‐ and C‐terminal binding, which stabilize a neurotoxic and neuroprotective protein conformation, respectively .…”

Section: The Possible Approaches To Directly Target α‐Syn Pathologymentioning

confidence: 86%

“…31 In line with epidemiological evidence supporting that cigarette smoking lowers the risk of PD, 32 nicotine, the main tobacco component has been found to display antifibrillogenic properties by inhibiting de novo α-syn oligomerization and fibril formation and destabilizing preformed α-syn fibrils in yeast. 33,34 Other molecules, including psychostimulants with amphetamine-like structure, as cocaine or methylphenidate, have been found to interact with α-syn with differential modalities, involving either the sole Nterminal portion or a contemporaneous N-and C-terminal binding, which stabilize a neurotoxic and neuroprotective protein conformation, respectively. 35 As the central region of α-syn (aa 61-95) is most important for the conformational shift of the protein to β-sheets, numerous small molecule inhibitors of α-syn aggregation were identified, thanks to in vitro assays as ligands of residues 69-72.…”

Section: The Possible Approaches To Directly Target α-Syn Pathologymentioning

confidence: 99%

The good and bad of therapeutic strategies that directly target α‐synuclein

et al. 2019

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Synucleinopathies are neurodegenerative diseases characterized by the accumulation of either neuronal/axonal or glial insoluble proteinaceous aggregates mainly composed of α‐synuclein (α‐syn). Among them, the most common disorders are Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and some forms of familial parkinsonism. Both α‐syn fibrils and oligomers have been found to exert toxic effects on neurons or oligodendroglial cells, can activate neuroinflammatory responses, and mediate the spreading of α‐syn pathology. This poses the question of which is the most toxic α‐syn species. What is worst, α‐syn appears as a very peculiar protein, exerting multiple physiological functions in neurons, especially at synapses, but without acquiring a stable tertiary structure. Its conformation is particularly plastic, and the protein can exist in a natively unfolded state (mainly in solution), partially α‐helical folded state (when it interacts with biological membranes), or oligomeric state (tetramers or dimers with debated functional profile). The extent of α‐syn expression impinges on the resilience of neuronal cells, as multiplications of its gene locus, or overexpression, can cause neurodegeneration and onset of motor phenotype. For these reasons, one of the main challenges in the field of synucleinopathies, which still nowadays can only be managed by symptomatic therapies, has been the development of strategies aimed at reducing α‐syn levels, oligomer formation, fibrillation, or cell‐to‐cell transmission. This review resumes the therapeutic approaches that have been proposed or are under development to counteract α‐syn pathology by direct targeting of this protein and discuss their pros and cons in relation to the current state‐of‐the‐art α‐syn biology.

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“…On the contrary, Ikeda et al observed that smoking diminish the chances of cognitive impairment and the risk for dementia [15]. In addition, Kardani et al proposed that the presence of nicotine in cigarettes activates the nicotinic acetylcholine receptors and stimulates its neuroprotective role and dopaminergic effect [16].…”

Section: Discussionmentioning

confidence: 99%

Gender-based clinical study on the association of cognitive impairment with drinking and smoking

Fu¹,

Chen²,

Zhang³

et al. 2018

Trop. J. Pharm Res

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Purpose: To evaluate the relationship between alcohol consumption and cigarette smoking among the elderly population of a Chinese city with a risk of developing cognitive decline and dementia. Methods: In this study, 1687 participants from the suburban town of Yanliang in Xi'an Sub-province, Shanxi Province, China in the age group of 60-65 years and who have not develop cognitive decline were assessed over a 6-year period. The study involved the evaluation of gender-based effect on alcohol consumption and smoking cigarette and its impact on cognitive functions. Results: The study observed that smokers have a higher risk of cognitive decline than non-smokers (odds ratio = 1.51; 95 % CI = (1.07-2.11). Interestingly, the odds ratio of the smokers among the female subjects was 1.54; 95 % CI (1.02-2.49) compared to female non-smokers. Moreover, a dosedependent relationship was observed for those female smoker with higher pack-years compared to nonsmokers (p = 0.003). On the other hand, regular alcohol consumption also increased the possibility of dementia and cognitive decline (odds ratio = 1.69; CI at 95 % = (1.03-2.75), hence a dose-dependent relationship was observed between male users (p = 0.042). Conclusion: The results suggest that alcohol consumption and smoking are linked with cognitive decline among the female subjects in the age group of 60-65 years. Thus, the relationship between these factors is characterized by gender difference which may be due to female sex hormones.

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Nicotine slows down oligomerisation of α-synuclein and ameliorates cytotoxicity in a yeast model of Parkinson's disease

Cited by 42 publications

References 56 publications

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy

Gamma synuclein is a novel nicotine responsive protein in oral cancer malignancy

The good and bad of therapeutic strategies that directly target α‐synuclein

Gender-based clinical study on the association of cognitive impairment with drinking and smoking

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