A pH-eQTL interaction at the RIT2-SYT4 Parkinson's disease risk locus in the substantia nigra

BACKGROUND: Parkinson's disease (PD) causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson's disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. OBJECTIVE: To assess pH associations at the RIT2-SYT4 locus. METHODS: Linear models to examine two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. RESULTS: Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain. Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the GTEx dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 was not seen. This null finding may be due to the short postmortem intervals (PMI) of the GTEx tissue samples. In the BrainEAC data, we tested the effect of PMI and only observed the interactions in the longer PMI samples. CONCLUSIONS: These previously unknown associations suggest novel mechanistic roles for rs12456492, RIT2, and SYT4 in the regulation of pH in the substantia nigra.

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A pH-eQTL Interaction at the RIT2–SYT4 Parkinson’s Disease Risk Locus in the Substantia Nigra

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.690632 ◽

2021 ◽

Vol 13 ◽

Author(s):

Sejal Patel ◽

Derek Howard ◽

Leon French

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Human Brain ◽

Disease Risk ◽

Brain Regions ◽

Dopamine Neurons ◽

Postmortem Human Brain ◽

Increased Risk

Parkinson’s disease causes severe motor and cognitive disabilities that result from the progressive loss of dopamine neurons in the substantia nigra. The rs12456492 variant in the RIT2 gene has been repeatedly associated with increased risk for Parkinson’s disease. From a transcriptomic perspective, a meta-analysis found that RIT2 gene expression is correlated with pH in the human brain. To assess these pH associations in relation to Parkinson’s disease risk, we examined the two datasets that assayed rs12456492, gene expression, and pH in the postmortem human brain. Using the BrainEAC dataset, we replicate the positive correlation between RIT2 gene expression and pH in the human brain (n = 100). Furthermore, we found that the relationship between expression and pH is influenced by rs12456492. When tested across ten brain regions, this interaction is specifically found in the substantia nigra. A similar association was found for the co-localized SYT4 gene. In addition, SYT4 associations are stronger in a combined model with both genes, and the SYT4 interaction appears to be specific to males. In the Genotype-Tissue Expression (GTEx) dataset, the pH associations involving rs12456492 and expression of either SYT4 and RIT2 were not seen. This null finding may be due to the short postmortem intervals of the GTEx tissue samples. In the BrainEAC data, we tested the effect of postmortem interval and only observed the interactions in samples with the longer intervals. These previously unknown associations suggest novel roles for rs12456492, RIT2, and SYT4 in the regulation and response to pH in the substantia nigra.

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A genetic and transcriptomic assessment of the KTN1 gene in Parkinson’s disease risk

10.1101/2021.03.08.21252688 ◽

2021 ◽

Author(s):

Anni Moore ◽

Sara Bandres-Ciga ◽

Cornelis Blauwendraat ◽

Monica Diez-Fairen

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Risk ◽

Association Studies ◽

Age At Onset ◽

Brain Regions ◽

Whole Genome Sequencing Data ◽

Genome Wide Association Studies ◽

Sequencing Data ◽

Increased Risk

AbstractParkinson’s disease (PD) is a progressive neurological disorder caused by both genetic and environmental factors. A recent finding has suggested an association between KTN1 genetic variants and changes in its expression in the putamen and substantia nigra brain regions and an increased risk for PD. Here, we examine the link between PD susceptibility and KTN1 using individual-level genotyping data and summary statistics from the most recent genome-wide association studies (GWAS) for PD risk and age at onset from the International Parkinson’s Disease Genomics Consortium (IPDGC), as well as whole-genome sequencing data from the Accelerating Medicines Partnership Parkinson’s disease (AMP-PD) initiative. To investigate the potential effect of changes in KTN1 expression on PD compared to healthy individuals, we further assess publicly available expression quantitative trait loci (eQTL) results from GTEx v8 and BRAINEAC and transcriptomics data from AMP-PD. Overall, we found no genetic associations between KTN1 and PD in our cohorts but found potential evidence of differences in mRNA expression, which needs to be further explored.

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Disease Duration Influences Gene Expression in Neuromelanin-Positive Cells From Parkinson’s Disease Patients

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.763777 ◽

2021 ◽

Vol 14 ◽

Author(s):

Katarína Tiklová ◽

Linda Gillberg ◽

Nikolaos Volakakis ◽

Hilda Lundén-Miguel ◽

Lina Dahl ◽

...

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Lewy Body Disease ◽

Dopamine Neurons ◽

Differentially Expressed ◽

Incidental Lewy Body Disease ◽

Advanced Stages ◽

Midbrain Dopamine

Analyses of gene expression in cells affected by neurodegenerative disease can provide important insights into disease mechanisms and relevant stress response pathways. Major symptoms in Parkinson’s disease (PD) are caused by the degeneration of midbrain dopamine (mDA) neurons within the substantia nigra. Here we isolated neuromelanin-positive dopamine neurons by laser capture microdissection from post-mortem human substantia nigra samples recovered at both early and advanced stages of PD. Neuromelanin-positive cells were also isolated from individuals with incidental Lewy body disease (ILBD) and from aged-matched controls. Isolated mDA neurons were subjected to genome-wide gene expression analysis by mRNA sequencing. The analysis identified hundreds of dysregulated genes in PD. Results showed that mostly non-overlapping genes were differentially expressed in ILBD, subjects who were early after diagnosis (less than five years) and those autopsied at more advanced stages of disease (over five years since diagnosis). The identity of differentially expressed genes suggested that more resilient, stably surviving DA neurons were enriched in samples from advanced stages of disease, either as a consequence of positive selection of a less vulnerable long-term surviving mDA neuron subtype or due to up-regulation of neuroprotective gene products.

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Epigenetic Study in Parkinson’s Disease: A Pilot Analysis of DNA Methylation in Candidate Genes in Brain

Cells ◽

10.3390/cells7100150 ◽

2018 ◽

Vol 7 (10) ◽

pp. 150 ◽

Cited By ~ 8

Author(s):

Luis Navarro-Sánchez ◽

Beatriz Águeda-Gómez ◽

Silvia Aparicio ◽

Jordi Pérez-Tur

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Dna Methylation ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Brain Regions ◽

Epigenetic Factors ◽

Promoter Regions ◽

Disease Pathogenesis ◽

Cpg Dinucleotides

Efforts have been made to understand the pathophysiology of Parkinson’s disease (PD). A significant number of studies have focused on genetics, despite the fact that the described pathogenic mutations have been observed only in around 10% of patients; this observation supports the fact that PD is a multifactorial disorder. Lately, differences in miRNA expression, histone modification, and DNA methylation levels have been described, highlighting the importance of epigenetic factors in PD etiology. Taking all this into consideration, we hypothesized that an alteration in the level of methylation in PD-related genes could be related to disease pathogenesis, possibly due to alterations in gene expression. After analysing promoter regions of five PD-related genes in three brain regions by pyrosequencing, we observed some differences in DNA methylation levels (hypo and hypermethylation) in substantia nigra in some CpG dinucleotides that, possibly through an alteration in Sp1 binding, could alter their expression.

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Gene expression profiling of substantia nigra dopamine neurons: further insights into Parkinson's disease pathology

Brain ◽

10.1093/brain/awn323 ◽

2008 ◽

Vol 132 (7) ◽

pp. 1795-1809 ◽

Cited By ~ 202

Author(s):

Filip Simunovic ◽

Ming Yi ◽

Yulei Wang ◽

Laurel Macey ◽

Lauren T. Brown ◽

...

Keyword(s):

Gene Expression ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Dopamine Neurons

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The Emerging Role of Neuropeptides in Parkinson’s Disease

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.646726 ◽

2021 ◽

Vol 13 ◽

Author(s):

Yanan Zheng ◽

Linlin Zhang ◽

Junxia Xie ◽

Limin Shi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Brain Regions ◽

Dopamine Neurons ◽

Age Related ◽

Pituitary Adenylate Cyclase ◽

New Strategy

Parkinson’s disease (PD), the second most common age-related neurodegenerative disease, results from the loss of dopamine neurons in the substantia nigra. This disease is characterized by cardinal non-motor and motor symptoms. Several studies have demonstrated that neuropeptides, such as ghrelin, neuropeptide Y, pituitary adenylate cyclase-activating polypeptide, substance P, and neurotensin, are related to the onset of PD. This review mainly describes the changes in these neuropeptides and their receptors in the substantia nigra-striatum system as well as the other PD-related brain regions. Based on several in vitro and in vivo studies, most neuropeptides play a significant neuroprotective role in PD by preventing caspase-3 activation, decreasing mitochondrial-related oxidative stress, increasing mitochondrial biogenesis, inhibiting microglial activation, and anti-autophagic activity. Thus, neuropeptides may provide a new strategy for PD therapy.

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Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters

10.1101/621680 ◽

2019 ◽

Author(s):

Rebecca D. Howell ◽

Sergio Dominguez-Lopez ◽

Sarah Ocañas ◽

Willard M. Freeman ◽

Michael J. Beckstead

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Substantia Nigra ◽

Disease Risk ◽

Brain Slices ◽

Dopamine Neuron ◽

Dopamine Neurons ◽

Central Feature ◽

Neuron Firing

SUMMARYThe degeneration of substantia nigra (SN) dopamine neurons is a central feature in the pathology associated with Parkinson’s disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinson’s disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. While much research in Parkinson’s has focused on the mechanisms underlying dopamine neuron degeneration, very little work has considered the influence of these two risk factors to disease risk and presentation. In this work, we performed whole cell patch clamp recordings in brain slices to study the alterations in intrinsic firing properties of single dopamine neurons in C57BL/6 mice across ages and between sexes. We observed a progressive decline in dopamine neuron firing activity in males by 18 months of age, while dopamine neurons from females remained largely unaffected. A semiquantitative analysis of midbrain dopamine neuron populations revealed a slight decrease only in substantia nigra dopamine neurons in males, while females did not change. This was also accompanied by increases in the expression of genes that have been linked to Parkinson’s including PTEN-induced kinase 1 (PINK1) in both males and females, and the ubiquitin ligase parkin, primarily in the substantia nigra of males. These impairments in dopamine neuron function in males may represent a vulnerability to further insults that could predispose these cells to neurodegenerative diseases such as in Parkinson’s.

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Neuroinflammation and protein pathology in Parkinson’s disease dementia

Acta Neuropathologica Communications ◽

10.1186/s40478-020-01083-5 ◽

2020 ◽

Vol 8 (1) ◽

Cited By ~ 1

Author(s):

Antonina Kouli ◽

Marta Camacho ◽

Kieren Allinson ◽

Caroline H. Williams-Gray

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

T Lymphocytes ◽

Substantia Nigra ◽

Amyloid Β ◽

Brain Regions ◽

Parkinson’S Disease Dementia ◽

Activated Microglia ◽

Cell Counts ◽

The Brain

AbstractParkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

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