Tau Pathology in Parkinson's Disease

Zhang, Xue; Gao, Fengmei; Wang, Dongdong; Li, Chao; Fu, Yi; He, Wei; Zhang, Jianmin

doi:10.3389/fneur.2018.00809

Cited by 147 publications

(117 citation statements)

References 85 publications

Supporting

Mentioning

109

Contrasting

Unclassified

Order By: Relevance

“…The genetic association between the 17q21.31 locus and PD is therefore surprising. While it is not rare for tauopathy to occur alongside α-synuclein inclusions in the substantia nigra 37,38 , aggregated Tau is not a typical neuropathological feature of this disorder 36 . Despite the genetic association with 17q21.31, the OR is substantially smaller for PD than for PSP (OR ~ 1.4-1.5 for H1, OR ~ 0.8 for H2) 5,39 , and there does not appear to be any association with the H1c sub-haplotype 40,41 , indicating that different 17q21.31 locus variants and mechanisms may underlie the relative risk for each disease.…”

Section: Introductionmentioning

confidence: 99%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh

Liu

et al. 2019

Preprint

View full text Add to dashboard Cite

Parkinson's disease (PD) and progressive supranuclear palsy (PSP) are clinically similar neurodegenerative movement disorders that display unique neuropathological features (i.e. Lewy body pathology and Tau pathology, respectively). While each disorder has distinct clinical and genetic risk factors, both are associated with the MAPT 17q.21.31 locus H1 haplotype. This suggests a pleiotropic effect of this genomic region. To better understand the genetic contribution of this region to these diseases, we fine-mapped the apparent pleiotropy of this locus. Our study indicates that PD and PSP are associated with different sub-haplotypes of the H1 clade. PDassociated sub-haplotypes were associated with altered LRRC37A copy number and expression, which, like other PD risk-associated genes, we hypothesize to be most relevant to astroglial function. In contrast, PSP was associated with grossly altered LD structure across the 17q21.31 locus, and risk-associated variants were found to impact chromatin structure in both neurons and microglia. We conclude that the contribution of the 17q21.31 locus to multiple disorders is a result of its structural and haplotypic complexity, which in turn impacts the regulation of multiple genes and neural cell types. This raises the possibility of novel disease-specific pathogenic mechanisms driven by 17q21.31 structural variation and altered epigenetic regulation that appear to converge on glial function and gene expression. By fine-mapping the association of H1 with PD and PSP, we have begun to untangle the apparent pleiotropy of this locus, and gain better insight into the mechanism of each disease, which will guide future functional analyses and disease models for PD and PSP.

show abstract

Section: Introductionmentioning

confidence: 99%

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

Bowles

Pugh

Liu

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…4 Although p-Tau links to the pathogenesis of AD and other Tauopathies, recent studies have revealed that p-Tau has a relationship with PD. 46 MAPT (encoded Tau protein) gene mutation in humans increases the risk of PD, and Tau aggregation and filaments have been observed in familial PD. P-Tau is also a component of Lewy bodies, which suggests that p-α-Synuclein and p-Tau have shared pathways or synergistic effect in the PD progression.…”

Section: Introductionmentioning

confidence: 99%

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Hu¹,

Hu²,

Liu³

et al. 2020

NDT

View full text Add to dashboard Cite

Parkinson's disease (PD) is the second most common neurodegenerative disease. The α-Synuclein is a major component of Lewy bodies and Lewy neurites, the pathologic hallmark of PD. It is known that α-Synuclein is phosphorylated (p-α-Synuclein) in PD and tau-hyperphosphorylation (p-Tau) is also a pathologic feature of PD. However, the relationship between p-Synuclein and p-Tau in PD is not clear, in particular in the MPTP model of PD. The purpose of this study was to reveal their relationship in the mouse MPTP model. Methods: Firstly, the p-α-Synuclein, α-Synuclein, p-Tau and Tau protein levels were analyzed. Then, GSK3β activation was determined using immunoblot and immunohistochemical staining. Finally, the dopaminergic neurodegeneration was assessed using Tyrosine Hydroxylase (TH) staining and retrograde labeling and microglial marker were labeled. Microglial activation and nigrostriatal pathway degeneration were observed. Results: The results showed that p-α-Synuclein, α-Synuclein, p-Tau and Tau were upregulated in both hippocampus and substantia nigra of the PD mouse model. Furthermore, p-α-Synuclein and p-Tau were localized in the same regions of substantial nigra (SN) and dentate gyrus (DG) of hippocampus (Hippo). The activated form of GSK3β (phosphor GSK3β Y216) was increased in multiple brain areas. The GSK3β inhibitor AZD1080 injected in MPTP mice suppressed the expression of p-Tau and p-GSK3β and improved motor functions. Conclusion: These findings revealed that p-α-Synuclein and p-Tau proteins are key pathological events leading to neurodegeneration and motor dysfunctions in the mouse MPTP model of PD. Our data suggest that the interference with the GSK3β activity may be an effective approach for the treatment of PD.

show abstract

“…This provides the rst evidence of an interaction between pesticide levels and rs11931074 of the SNCA gene on PD risk, although such a relationship has been demonstrated for the rs3775423 polymorphism and pesticide exposure [33]. The MAPT gene primarily encodes Tau protein, which is implicated in PD [34,35]. A study demonstrated that interaction between MAPT rs16940758 or rs2435211 and exposure to pesticides had no signi cant effect on PD either [33].…”

Section: Discussionmentioning

confidence: 81%

Interaction Between Genetic Variants and Serum Levels of Organochlorine Pesticides Contributes to Parkinson’s Disease

Xu¹,

Yang²,

Qian³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: There is evidence that genetic and environmental factors contribute to the onset and progression of Parkinson’s disease (PD). Pesticides are a class of environmental toxins that are linked to increased risk of PD. However, few studies have investigated the interaction between specific pesticides and genetic variants related to PD in the Chinese population.Methods: In this cross-sectional study, 19 serum levels of pesticides were measured. In addition, we also analyzed the interaction between specific pesticides and candidate genetic variants for PD. Finally, we investigated the mechanistic basis for the association between pesticides and increased risk of PD.Results: Serum levels of organochlorine pesticides including α-hexachlorocyclohexane (α-HCH), β-HCH, γ-HCH, δ-HCH, propanil, heptachlor, dieldrin, hexachlorobenzene, p,p’-dichlorodiphenyltrichloroethane (p,p’-DDE) and o,p’-dichloro-diphenyl-trichloroethane (o,p’-DDT) were higher in PD patients than in controls. α-HCH and propanil levels were associated with increased PD risk. Serum levels of dieldrin were associated with Hamilton Depression Scale and Montreal Cognitive Assessment scores in PD patients. The interaction between rs11931074 in α-synuclein (SNCA) and α-HCH or β-HCH, respectively, as well as rs16940758 in the microtubule-associated protein tau (MAPT) gene and δ-HCH were related to increased risk of PD. In addition, α-HCH and propanil enhanced the production of reactive oxygen species and decreased of mitochondrial membrane potential. Propanil but not α-HCH induced the aggregation of α-synuclein.Conclusions: Elevated serum levels of α-HCH and propanil are associated with increased risk of PD. Serum levels of dieldrin were associated with depression and cognitive function in PD patients. The interaction between genetic variants and pesticides also increased the risk of PD. Effects of genetic variants and pesticides on the risk of PD should be studied in more detail with a larger sample size to further understand the mechanisms involved.

show abstract

Tau Pathology in Parkinson's Disease

Cited by 147 publications

References 85 publications

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson’s disease are associated with LRRC37A/2 expression in astrocytes

<p>Phosphorylation of Tau and α-Synuclein Induced Neurodegeneration in MPTP Mouse Model of Parkinson’s Disease</p>

Interaction Between Genetic Variants and Serum Levels of Organochlorine Pesticides Contributes to Parkinson’s Disease

Contact Info

Product

Resources

About