Parkinson’s disease (PD) is a neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. Mutations in the
PINK1
gene result in an autosomal recessive form ...of early-onset PD. PINK1 plays a vital role in mitochondrial quality control via the removal of dysfunctional mitochondria. The aim of the present study was to create a cellular model of PD using siRNA-mediated knock down of PINK1 in SH-SY5Y neuroblastoma cells The possible protective effects of curcumin, known for its many beneficial properties including antioxidant and anti-inflammatory effects, was tested on this model in the presence and absence of paraquat, an additional stressor.
PINK1
siRNA and control cells were separated into four treatment groups: (i) untreated, (ii) treated with paraquat, (iii) pre-treated with curcumin then treated with paraquat, or (iv) treated with curcumin. Various parameters of cellular and mitochondrial function were then measured. The
PINK1
siRNA cells exhibited significantly decreased cell viability, mitochondrial membrane potential (MMP), mitochondrial respiration and ATP production, and increased apoptosis. Paraquat-treated cells exhibited decreased cell viability, increased apoptosis, a more fragmented mitochondrial network and decreased MMP. Curcumin pre-treatment followed by paraquat exposure rescued cell viability and increased MMP and mitochondrial respiration in control cells, and significantly decreased apoptosis and increased MMP and maximal respiration in
PINK1
siRNA cells. These results highlight a protective effect of curcumin against mitochondrial dysfunction and apoptosis in PINK1-deficient and paraquat-exposed cells. More studies are warranted to further elucidate the potential neuroprotective properties of curcumin.
DJ-1 forms part of the neuronal cellular defence mechanism against oxidative insults, due to its ability to undergo self-oxidation. Oxidative stress has been implicated in the pathogenesis of central ...nervous system damage in different neurodegenerative disorders including Alzheimer's disease and Parkinson's disease (PD). Various mutations in the DJ-1 (PARK7) gene have been shown to cause the autosomal recessive form of PD. In the present study South African PD patients were screened for mutations in DJ-1 and we aimed to investigate the functional significance of a novel 16 bp deletion variant identified in one patient.
The possible effect of the deletion on promoter activity was investigated using a Dual-Luciferase Reporter assay. The DJ-1 5'-UTR region containing the sequence flanking the 16 bp deletion was cloned into a pGL4.10-Basic luciferase-reporter vector and transfected into HEK293 and BE(2)-M17 neuroblastoma cells. Promoter activity under hydrogen peroxide-induced oxidative stress conditions was also investigated. Computational (in silico) cis-regulatory analysis of DJ-1 promoter sequence was performed using the transcription factor-binding site database, TRANSFAC via the PATCH and rVISTA platforms.
A novel 16 bp deletion variant (g.-6_+10del) was identified in DJ-1 which spans the transcription start site and is situated 93 bp 3' from a Sp1 site. The deletion caused a reduction in luciferase activity of approximately 47% in HEK293 cells and 60% in BE(2)-M17 cells compared to the wild-type (P < 0.0001), indicating the importance of the 16 bp sequence in transcription regulation. The activity of both constructs was up-regulated during oxidative stress. Bioinformatic analysis revealed putative binding sites for three transcription factors AhR, ARNT, HIF-1 within the 16 bp sequence. The frequency of the g.-6_+10del variant was determined to be 0.7% in South African PD patients (2 heterozygotes in 148 individuals).
This is the first report of a functional DJ-1 promoter variant, which has the potential to influence transcript stability or translation efficiency. Further work is necessary to determine the extent to which the g.-6_+10del variant affects the normal function of the DJ-1 promoter and whether this variant confers a risk for PD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Keywords: Parkinson's disease; genetics; genome-wide association; mutation Article Note: Correction added on 6 February 2021, after first online publication: copyright line updated. Relevant ...conflicts of interest/financial disclosures: Dr. Singleton is supported by the Intramural Research Program of the National Institute on Aging and has received grant support from the Michael J. Fox Foundation for Parkinson's Research and the Aligning Science Across Parkinson's Initiative. He has received royalty payments related to a diagnostic for stroke. Dr. Blauwendraat is supported by the Intramural Research Program of the National Institute on Aging and has received grant support from the Michael J. Fox Foundation for Parkinson's Research and the Aligning Science Across Parkinson's Initiative.
Altered levels of mitochondrial DNA copy number (mtDNA-CN) have been proposed as a proxy for mitochondrial dysfunction. Following reports of mtDNA depletion in the blood and substantia nigra of ...Parkinson's disease (PD) cases, mtDNA-CN was also suggested as a possible biomarker for PD. Therefore, this study aimed to investigate whether blood mtDNA-CN levels of African ancestry PD cases would be altered compared to controls, as previously reported in individuals of Asian and European ancestry.
Droplet digital polymerase chain reaction (ddPCR) was performed to quantify blood-derived mtDNA-CN levels as a ratio of a mitochondrial gene (MT-TL1) to a nuclear gene (B2M) in 72 PD cases and 79 controls of African ancestry (i.e. individuals with African mtDNA haplogroups) from South Africa. mtDNA-CN per cell was calculated by the formula 2 × MT-TL1/B2M.
Accepting study limitations, we report significantly higher mtDNA-CN in whole blood of our PD cases compared to controls (median difference = 81 copies/cell), independent of age (95% CI 64, 98; P < 0.001). These findings contradict previous reports of mtDNA depletion in PD cases.
We caution that the observed differences in mtDNA-CN between the present and past studies may be a result of unaccounted-for factors and variability in study designs. Consequently, larger well-designed investigations may help determine whether mtDNA-CN is consistently altered in the blood of PD cases across different ancestries and whether it can serve as a viable biomarker for PD.
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•mtDNA-CN was quantified in African ancestry PD cases and controls using ddPCR.•PD cases had significantly higher levels of mtDNA-CN than controls.•Age-adjusted analysis revealed 81 mtDNA copies/cell more in cases than controls.•Variability of blood mtDNA-CN may limit its use as a PD biomarker.
The African Society of Human Genetics (AfSHG) was formed to provide a forum for human genetics and genomics scientists in Africa to interact, network, and collaborate. This is critical to facilitate ...development of solutions to the public health burden of many rare and common diseases across the continent. AfSHG fully supports the Black Lives Matter movement, which is dedicated to fighting racism and ensuring that society values the lives and humanity of Black people. The AfSHG would like to add its “voice” to the public outcry against racism sparked by George Floyd’s death and to declare its commitment to ensuring that injustice and systematic racism, as well as abuse and exploitation of Africans and their biological material, are no longer tolerated. This is particularly relevant now as African genomic variation is poised to make significant contributions across several disciplines including ancestry, personalized medicine, and novel drug discovery. “Black Lives Matter and Black Research Matters” is AfSHG’s call for the global community to support halting, and reversing, the perpetuation of exploitation of African people through neocolonial malpractices in genomic research. We also propose five key ways to curb racism in science, so that we can move forward together, with a common humanity, collectively embracing scientific endeavors.
Abstract Metabolic syndrome (MetS) is a cluster of factors that increases the risk of cardiovascular disease (CVD), one of the leading causes of mortality in patients with schizophrenia. Incidence ...rates of MetS are significantly higher in patients with schizophrenia compared to the general population. Several factors contribute to this high comorbidity. This systematic review focuses on genetic factors and interrogates data from association studies of genes implicated in the development of MetS in patients with schizophrenia. We aimed to identify variants that potentially contribute to the high comorbidity between these disorders. PubMed, Web of Science and Scopus databases were accessed and a systematic review of published studies was conducted. Several genes showed strong evidence for an association with MetS in patients with schizophrenia, including the fat mass and obesity associated gene ( FTO ), leptin and leptin receptor genes ( LEP , LEPR ), methylenetetrahydrofolate reductase ( MTHFR ) gene and the serotonin receptor 2C gene ( HTR2C ). Genetic association studies in complex disorders are convoluted by the multifactorial nature of these disorders, further complicating investigations of comorbidity. Recommendations for future studies include assessment of larger samples, inclusion of healthy controls, longitudinal rather than cross-sectional study designs, detailed capturing of data on confounding variables for both disorders and verification of significant findings in other populations. In future, big genomic datasets may allow for the calculation of polygenic risk scores in risk prediction of MetS in patients with schizophrenia. This could ultimately facilitate early, precise, and patient-specific pharmacological and non-pharmacological interventions to minimise CVD associated morbidity and mortality.
Parkinson's disease (PD) incidence is increasing in sub‐Saharan Africa. We recruited 687 individuals with PD from different ancestral groups across South Africa. More Afrikaner Europeans had ...early‐onset PD than other ancestral groups. More men had PD than women, with a younger age at onset for men (56 years).
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