Nrf2 and Parkinson’s Disease

Parkinson’s disease (PD) results from a complex interaction of environmental and genetic influences on a background of aging. Regardless of etiology, significant clinical advances rely on identifying the common biological pathways that underpin neuronal degeneration. Oxidative stress is consistently reported as a hallmark feature of PD. Recently, it has been demonstrated that Nrf2 modulation can protect neurons from parkinsonian agents and, in some instances, reverse motor symptoms of animal models. Furthermore, baseline aberrations of Nrf2 and its associated pathway have been reported in PD patients, and genetic variability—within and around the Nrf2 gene—may modify PD susceptibility and onset. Overall, Nrf2 dysregulation has been tentatively implicated in the pathogenesis of PD and may prove to be an effective therapeutic target

Parkinson's Disease in Relation to Pesticide Exposure and Nuclear Encoded Mitochondrial Complex I Gene Variants

Parkinson's disease (PD) is a common age-related neurodegenerative disorder thought to result from the integrated effects of genetic background and exposure to neuronal toxins. Certain individual nuclear-encoded mitochondrial complex I gene polymorphisms were found to be associated with ∼ 2-fold risk variation in an Australian case-control sample. We further characterized this sample of 306 cases and 321 controls to determine the mutual information contained in the 22 SNPs and, additionally, level of pesticide exposure: five distinct risk sets were identified using grade-of-membership analysis. Of these, one was robust to pesticide exposure (I), three were vulnerable (II, III, IV), and another (V) denoted low risk for unexposed persons. Risk for individual subjects varied > 16-fold according to level of membership in the vulnerable groups. We conclude that inherited variation in mitochondrial complex I genes and pesticide exposure together modulate risk for PD

Oxidative Stress in Parkinson\u27s Disease; Parallels Between Current Animal Models, Human Studies and Cells

Griffith Sciences, Griffith Institute for Drug DiscoveryFull Tex

GPNN: Power Studies and Applications of a Neural Network Method for Detecting Gene-Gene Interactions in Studies of Human Disease

The identification and characterization of genes that influence the risk of common, complex multifactorial disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. We have previously introduced a genetic programming optimized neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of gene combinations associated with disease risk. The goal of this study was to evaluate the power of GPNN for identifying high-order gene-gene interactions. We were also interested in applying GPNN to a real data analysis in Parkinson\u27s disease

Singing for people with Parkinson's disease

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To compare the efficacy and effectiveness of singing interventions with non‐singing intervention or usual care on QoL, wellbeing, and speech and communication among people with PD. We will assess the QoL and the physical, psychological, and social health and wellbeing of people with PD who receive a singing intervention, compared to non‐singing intervention or usual care

Plasma biomarkers inclusive of α-synuclein/amyloid-beta40 ratio strongly correlate with Mini-Mental State Examination score in Parkinson's disease and predict cognitive impairment

Plasma biomarkers for Parkinson’s disease (PD) diagnosis that carry predictive value for cognitive impairment are valuable. We explored the relationship of Mini-Mental State Examination (MMSE) score with plasma biomarkers in PD patients and compared results to vascular dementia (VaD) and normal controls. The predictive accuracy of an individual biomarker on cognitive impairment was evaluated using area under the receiver operating characteristic curve (AUROC), and multivariate logistic regression was applied to evaluate predictive accuracy of biomarkers on cognitive impairment; 178 subjects (41 PD, 31 VaD and 106 normal controls) were included. In multiple linear regression analysis of PD patients, α-synuclein, anti-α-synuclein, α-synuclein/Aβ40 and anti-α-synuclein/Aβ40 were highly predictive of MMSE score in both full model and parsimonious model (R2 = 0.838 and 0.835, respectively) compared to non-significant results in VaD group (R2 = 0.149) and in normal controls (R2 = 0.056). Α-synuclein and anti-α-synuclein/Aβ40 were positively associated with MMSE score, and anti-α-synuclein, α-synuclein/Aβ40 were negatively associated with the MMSE score among PD patients (all Ps < 0.005). In the AUROC analysis, anti-α-synuclein (AUROC = 0.788) and anti-α-synuclein/Aβ40 (AUROC = 0.749) were significant individual predictors of cognitive impairment. In multivariate logistic regression, full model of combined biomarkers showed high accuracy in predicting cognitive impairment (AUROC = 0.890; 95%CI 0.796–0.984) for PD versus controls, as was parsimonious model (AUROC = 0.866; 95%CI 0.764–0.968). In conclusion, simple combination of biomarkers inclusive of α-synuclein/Aβ40 strongly correlates with MMSE score in PD patients versus controls and is highly predictive of cognitive impairment

α-Synuclein aggregation inhibitory activity of the bromotyrosine derivatives aerothionin and aerophobin-2 from the subtropical marine sponge Aplysinella sp

The neuronal protein α-synuclein (α-syn) is one of the main constituents of intracellular amyloid aggregations found in the post-mortem brains of Parkinson’s disease (PD) patients. Recently, we screened the MEOH extracts obtained from 300 sub-tropical marine invertebrates for α-syn binding activity using affinity MS and this resulted in the extract of the Verongida marine sponge Aplysinella sp. 1194, (QM G339263) displaying molecules that bind to the protein. The subsequent bioassay-guided separation of the Aplysinella sp. extract led to the isolation of the known bromotyrosine derivatives (+)-aerothionin (1) and (+)-aerophobin-2 (2). Both compounds bind to α-syn as detected by a MS affinity assay and inhibit α-syn aggregation in an assay that uses the fluorescence probe, thioflavin T, to detect aggregation. (+)-Aerothionin (1) was toxic to primary dopaminergic neurons at its expected α-syn aggregation inhibitory concentration and so could not be tested for pSyn aggregates in this functional assay. (+)-Aerophobin-2 (2) was not toxic and shown to weakly inhibit pSyn aggregation in primary dopaminergic neurons at 10 µM.Peer reviewe

Hesperine, a new imidazole alkaloid and α-synuclein binding activity of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine from the marine sponge Clathria (Thalysias) cf. hesperia

During a high-throughput screen of 300 Australian marine invertebrate extracts, the extract of the marine sponge Clathria (Thalysias) cf. hesperia was identified with α-synuclein binding activity. The bioassay-guided purification of this extract resulted in the isolation of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine (2) as the α-syn binder along with one new compound, hesperine (1), and five known compounds, indole-3-carboxaldehyde (3), (Z)-2'-demethylaplysinopsin (4), 2-amino-4'-hydroxyacetophenone (5), 4-hydroxybenzoic acid (6) and 4-hydroxybenzaldehyde (7). Herein, we report the structure elucidation of hesperine (1) and α-syn binding activity of 1-methyl-1,2,7,8-tetrahydro-2,8-dioxoadenosine (2).Peer reviewe

Editorial: Celebrating the Diversity of Genetic Research to Dissect the Pathogenesis of Parkinson's Disease

Parkinson's disease (PD) is the fastest growing neurological disorder worldwide, taking into account age-standardized rates for prevalence, disability and deaths (1). PD is characterized by a clinical symptomatology involving both motor and non-motor symptoms. According to the Global Burden of Disease study (2018), the global burden of this disorder has more than doubled over the past two decades from 2.5 million patients in 1990 to 6.1 million patients in 2016 (2). In this editorial and eBook, we highlight the research done on PD by members of a global consortium known as the Genetic Epidemiology of Parkinson's disease (GEoPD) Consortium. We begin the editorial by providing a brief history of how GEoPD was started and how it has subsequently developed into an international endeavor. We then briefly summarize the completed and ongoing projects, and conclude with the future vision of this unique consortium