MAPT rs242562 and GSK3B rs334558 are associated with Parkinson’s Disease in central China

Yu, Lan; Huang, Jinsha; Zhai, Desheng; Liu, Ling; Guo, Kexin; Liu, Xi; Xiong, Jing; Zhang, Zhentao; Wang, Youpei; Zhao, Ying; Wu, Ping; Wang, Dingan; Lin, Zhicheng; Wu, Jing; Xiong, Nian; Wang, Tao

doi:10.1186/1471-2202-15-54

Cited by 10 publications

(4 citation statements)

References 23 publications

(27 reference statements)

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“…However, the effects of ROCK and ROCK inhibitors on Bcl-2 in different types of cells have been controversial (Hippenstiel and others 2002; Ikeda and others 2003; Koch and others 2014), and no data have been published on the effect of ROCK inhibition on Bcl-2 in PD models or dopaminergic neurons. A number of previous studies have suggested the association between GSK-3β and PD (Duka and others 2007; Hernandez-Baltazar and others 2013; Yu and others 2014), and GSK-3β inhibitors have been suggested as potential therapeutic agents for the treatment of PD (Morales-Garcia and others 2013). Interestingly, it has been observed that ROCK inhibitors also inactivated GSK-3β in several types of cells (Hamano and others 2012).…”

Section: Mechanisms Involved In Rock-induced Dopaminergic Vulnerabilimentioning

confidence: 99%

Rho Kinase and Dopaminergic Degeneration

et al. 2014

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The small GTP-binding protein Rho plays an important role in several cellular functions. RhoA, which is a member of the Rho family, initiates cellular processes that act on its direct downstream effector Rho-associated kinase (ROCK). ROCK inhibition protects against dopaminergic cell death induced by dopaminergic neurotoxins. It has been suggested that ROCK inhibition activates neuroprotective survival cascades in dopaminergic neurons. Axon-stabilizing effects in damaged neurons may represent another mechanism of neuroprotection of dopaminergic neurons by ROCK inhibition. However, it has been shown that microglial cells play a crucial role in neuroprotection by ROCK inhibition and that activation of microglial ROCK mediates major components of the microglial inflammatory response. Additional mechanisms such as interaction with autophagy may also contribute to the neuroprotective effects of ROCK inhibition. Interestingly, ROCK interacts with several brain factors that play a major role in dopaminergic neuron vulnerability such as NADPH-oxidase, angiotensin, and estrogen. ROCK inhibition may provide a new neuroprotective strategy for Parkinson's disease. This is of particular interest because ROCK inhibitors are currently used against vascular diseases in clinical practice. However, it is necessary to develop more potent and selective ROCK inhibitors to reduce side effects and enhance the efficacy.

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Section: Mechanisms Involved In Rock-induced Dopaminergic Vulnerabilimentioning

confidence: 99%

Rho Kinase and Dopaminergic Degeneration

et al. 2014

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“…As one of the isoforms of GSK-3, GSK3 β is widely expressed in tissues, especially in the brain [ 19 ]. GSK3 β , an important pathogenic protein kinase for PD, is activated by phosphorylation of Try216 residue located in the kinase domain and inactivated by protein kinase B- (Akt-) mediated phosphorylation of Ser9 residue [ 20 , 21 ]. GSK3 β is well-known for its role on glycogen metabolism, activation of transcription factors, and phosphorylation of tau proteins [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

miR-135b Plays a Neuroprotective Role by Targeting GSK3β in MPP⁺-Intoxicated SH-SY5Y Cells

et al. 2017

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miR-135a-5p was reported to play a crucial role in the protective effects of hydrogen sulfide against Parkinson's disease (PD) by targeting rho-associated protein kinase 2 (ROCK2). However, the role of another member of miR-135 family (miR-135b) and the underlying mechanism in PD are still unclear. qRT-PCR and western blot showed that miR-135 was downregulated and glycogen synthase kinase 3β (GSK3β) was upregulated at mRNA and protein levels in MPP+-intoxicated SH-SY5Y cells in a dose- and time-dependent manner. MTT, TUNEL, and ELISA assays revealed that miR-135b overexpression significantly promoted cell proliferation and inhibited apoptosis and production of TNF-α and IL-1β in SH-SY5Y cells in the presence of MPP+. Luciferase reporter assay demonstrated that GSK3β was a direct target of miR-135b. Moreover, sodium nitroprusside (SNP), a GSK3β activator, dramatically reversed the effects of miR-135b upregulation on cell proliferation, apoptosis, and inflammatory cytokine production in MPP+-intoxicated SH-SY5Y cells. Taken together, miR-135b exerts a protective role via promotion of proliferation and suppression of apoptosis and neuroinflammation by targeting GSK3β in MPP+-intoxicated SH-SY5Y cells, providing a potential therapeutic target for the treatment of PD.

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“…Nine of these variants were linked to PD in at least two independent, unrelated cohort studies. They comprise: rs13312, a variant in the 3′-untranslated region of the ubiquitin-specific protease 24 gene ( USP24 ), associated with (PARK10) 85 , 86 , a susceptibility locus for PD; rs3766606, an intronic modification in the deglycase gene ( PARK7 ), linked with parkinsonism in Chinese and European populations 87 , 88 ; rs1801474 and rs1801582, two missense variants in the parkin RBR E3 ubiquitin-protein ligase gene (PRKN ), associated with PD risk 89 – 91 ; rs1800497, often correlated with neurological disorders, including PD, is located in the coding region of the ankyrin repeat and kinase domain containing the gene ( ANKK1 ), which controls dopamine synthesis in the brain 50 , 92 , 93 ; rs1801133, in the methylenetetrahydrofolate reductase gene ( MTHFR ), possibly implicated in PD 61 , 65 ; rs334558, a polymorphism in the glycogen synthase kinase 3 beta gene ( GSK3B ) potentially a protective factor for PD in Asian populations 94 , 95 ; rs6280, in the dopamine receptor D3 gene ( DRD3 ), implicated in both PD vulnerability and motor complications 96 , 97 ; and rs242562, a polymorphism in the microtubule-associated protein tau gene ( MAPT ), associated with PD 98 .…”

Section: Methodsmentioning

confidence: 99%

Differences in MTHFR and LRRK2 variant’s association with sporadic Parkinson’s disease in Mexican Mestizos correlated to Native American ancestry

Romero-Gutiérrez

Vázquez-Cárdenas

Moreno-Macías

et al. 2021

npj Parkinsons Dis.

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Parkinson’s disease (PD), a common neurodegenerative disorder, has a complex etiology where environmental and genetic factors intervene. While a number of genes and variants have been identified in recent decades as causative or protective agents of this condition, a limited number of studies have been conducted in mixed populations, such as Mexican Mestizos. The historical convergence of two founding groups and three ethnicities, and the increasing north-to-south gradient of Native American ancestry in Mexico resulted in a subpopulation structure with considerable genetic diversity. In this work, we investigate the influence of 21 known susceptibility variants for PD. Our case–control study, with a cohort of 311 Mexican Mestizo subjects, found a significant risk association for the variant rs1491942 in LRRK2. However, when stratification by ancestry was performed, a risk effect for MTHFR rs1801133 was observed only in the group with the highest percentage of European ancestry, and the PD risk effect for LRRK2 rs1491942 was significant in subjects with a higher ratio of Native American ancestry. Meta-analyses of these SNP revealed the effect of LRRK2 rs1491942 to be even more significant than previously described in populations of European descent. Although corroboration is necessary, our findings suggest that polymorphism rs1491942 may be useful as a risk marker of PD in Mexican Mestizos with greater Native American ancestry. The absence of associations with the remaining known risk factors is, in itself, a relevant finding and invites further research into the shared risk factors’ role in the pathophysiological mechanisms of this neurodegenerative disorder.

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MAPT rs242562 and GSK3B rs334558 are associated with Parkinson’s Disease in central China

Cited by 10 publications

References 23 publications

Rho Kinase and Dopaminergic Degeneration

Rho Kinase and Dopaminergic Degeneration

miR-135b Plays a Neuroprotective Role by Targeting GSK3β in MPP⁺-Intoxicated SH-SY5Y Cells

Differences in MTHFR and LRRK2 variant’s association with sporadic Parkinson’s disease in Mexican Mestizos correlated to Native American ancestry

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MAPT rs242562 and GSK3B rs334558 are associated with Parkinson’s Disease in central China

Cited by 10 publications

References 23 publications

Rho Kinase and Dopaminergic Degeneration

Rho Kinase and Dopaminergic Degeneration

miR-135b Plays a Neuroprotective Role by Targeting GSK3β in MPP+-Intoxicated SH-SY5Y Cells

Differences in MTHFR and LRRK2 variant’s association with sporadic Parkinson’s disease in Mexican Mestizos correlated to Native American ancestry

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miR-135b Plays a Neuroprotective Role by Targeting GSK3β in MPP⁺-Intoxicated SH-SY5Y Cells