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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.

Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Parkinson’s disease (PD) is a movement disorder associated with severe loss of mainly dopaminergic neurons in the substantia nigra. Pathological hallmarks include Lewy bodies, and loss of neuromelanin, due to degeneration of neuromelanin-containing dopaminergic neurons. Despite being described over 200 years ago, the etiology of PD remains unknown. Here, we highlight the roles of reactive oxygen species (ROS), iron, alpha synuclein (α-syn) and neuromelanin in a toxic feedback loop culminating in neuronal death and spread of the disease. Dopaminergic neurons are particularly vulnerable due to decreased antioxidant concentration with aging, constant exposure to ROS and presence of neurotoxic compounds (e.g. ortho-quinones). ROS and iron increase each other’s levels, creating a state of oxidative stress. α-Syn aggregation is influenced by ROS and iron but also increases ROS and iron via its induced mitochondrial dysfunction and ferric-reductase activity. Neuromelanin’s binding affinity is affected by increased ROS and iron. Furthermore, during neuronal death, neuromelanin is degraded in the extracellular space, releasing its bound toxins. This cycle of events continues to neighboring neurons in the form of a toxic loop, causing PD pathology. The increase in ROS and iron may be an important target for therapies to disrupt this toxic loop, and therefore diets rich in certain ‘nutraceuticals’ may be beneficial. Turmeric is an attractive candidate, as it is known to have anti-oxidant and iron chelating properties. More studies are needed to test this theory and if validated, this would be a step towards development of lifestyle-based therapeutic modalities to complement existing PD treatments.

A pathological hallmark of the neurodegenerative disorder, Parkinson's disease (PD), is aggregation of toxic forms of the presynaptic protein, α-synuclein in structures known as Lewy bodies. α-Synuclein pathology is found in both the brain and gastrointestinal tracts of affected individuals, possibly due to the movement of this protein along the vagus nerve that connects the brain to the gut. In this review, we discuss current insights into the spread of α-synuclein pathology along the gut-brain axis, which could be targeted for therapeutic interventions. The prion-like propagation of α-synuclein, and the clinical manifestations of gastrointestinal dysfunction in individuals living with PD, are discussed. There is currently insufficient evidence that surgical alteration of the vagus nerve, or removal of gut-associated lymphoid tissues, such as the appendix and tonsils, are protective against PD. Furthermore, we propose curcumin as a potential candidate to prevent the spread of α-synuclein pathology in the body by curcumin binding to α-synuclein's non-amyloid β-component (NAC) domain. Curcumin is an active component of the food spice turmeric and is known for its antioxidant, anti-inflammatory, and potentially neuroprotective properties. We hypothesize that once α-synuclein is bound to curcumin, both molecules are subsequently excreted from the body. Therefore, dietary supplementation with curcumin over one's lifetime has potential as a novel approach to complement existing PD treatment and/or prevention strategies. Future studies are required to validate this hypothesis, but if successful, this could represent a significant step towards improved nutrient-based therapeutic interventions and preventative strategies for this debilitating and currently incurable disorder.

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.

Over the past four decades, mitochondrial dysfunction has been a recurring theme in Parkinson's disease (PD) and is hypothesized to play a central role in its disease pathogenesis. Given the instrumental role of mitochondria in cellular energy production, their dysfunction can be detrimental to highly energy-dependent dopaminergic neurons, known to degenerate in PD. Mitochondria harbor multiple copies of their own genomes (mtDNA), encoding critical respiratory chain complexes required for energy production. Consequently, mtDNA has been investigated as a source of mitochondrial dysfunction in PD. As seen in multiple mitochondrial diseases, deleterious mtDNA variation and mtDNA copy number depletion can impede mtDNA protein synthesis, leading to inadequate energy production in affected cells and the onset of a disease phenotype. As such, high burdens of mtDNA defects but also mtDNA depletion, previously identified in the substantia nigra of PD patients, have been suggested to play a role in PD. Genetic variation in nuclear DNA encoding factors required for replicating, transcribing, and translating mtDNA, could underlie these observed mtDNA changes. Herein we examine this possibility and provide an overview of studies that have investigated whether nuclear-encoded genes associated with mtDNA processes may influence PD risk. Overall, pathway-based analysis studies, mice models, and case reports of mitochondrial disease patients manifesting with parkinsonism all implicate genes encoding factors related to mtDNA processes in neurodegeneration and PD. Most notably, cumulative genetic variation in these genes likely contributes to neurodegeneration and PD risk by acting together in common pathways to disrupt mtDNA processes or impair their regulation. © 2021 International Parkinson and Movement Disorder Society © 2021 International Parkinson and Movement Disorder Society.

Parkinson's disease (PD) is a neurodegenerative movement disorder, affecting 1-2% of the human population over 65. A previous study by our group identified a p.G849D variant in neurexin 2α (NRXN2) co-segregating with PD, prompting validation of its role using experimental methods. This novel variant had been found in a South African family with autosomal dominant PD. NRXN2α is an essential synaptic maintenance protein with multiple functional roles at the synaptic cleft. The aim of the present study was to investigate the potential role of the translated protein NRXN2α and the observed mutant in PD by performing functional studies in an in vitro model. Wild-type and mutant NRXN2α plasmids were transfected into SH-SY5Y cells to assess the effect of the mutant on cell viability and apoptosis [(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) Assay; ApoTox-Glo™ Triplex Assay)], mitochondrial membrane potential (MMP; MitoProbe™ JC-1 Assay), mitochondrial network analysis (MitoTracker

Human genetics research lacks diversity; over 80% of genome-wide association studies have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine.This systematic review provides an overview of research involving Parkinson's disease (PD) genetics in underrepresented populations (URP) and sets a baseline to measure the future impact of current efforts in those populations.We searched PubMed and EMBASE until October 2021 using search strings for "PD," "genetics," the main "URP," and and the countries in Latin America, Caribbean, Africa, Asia, and Oceania (excluding Australia and New Zealand). Inclusion criteria were original studies, written in English, reporting genetic results on PD from non-European populations. Two levels of independent reviewers identified and extracted information.We observed imbalances in PD genetic studies among URPs. Asian participants from Greater China were described in the majority of the articles published (57%), but other populations were less well studied; for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just nine studies using a genome-wide approach published up to 2021, including URPs.This review provides insight into the significant lack of population diversity in PD research highlighting the immediate need for better representation. The Global Parkinson's Genetics Program (GP2) and similar initiatives aim to impact research in URPs, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future. © 2022 International Parkinson and Movement Disorder Society.

Evidence suggests that shared pathophysiological mechanisms in neuropsychiatric disorders (NPDs) may contribute to risk and resilience. We used single-gene and network-level transcriptomic approaches to investigate shared and disorder-specific processes underlying posttraumatic stress disorder (PTSD), Parkinson’s disease (PD) and schizophrenia in a South African sample. RNA-seq was performed on blood obtained from cases and controls from each cohort. Gene expression and weighted gene correlation network analyses (WGCNA) were performed using DESeq2 and CEMiTool, respectively. Significant differences in gene expression were limited to the PTSD cohort. However, WGCNA implicated, amongst others, ribosomal expression, inflammation and ubiquitination as key players in the NPDs under investigation. Differential expression in ribosomal-related pathways was observed in the PTSD and PD cohorts, and focal adhesion and extracellular matrix pathways were implicated in PD and schizophrenia. We propose that, despite different phenotypic presentations, core transdiagnostic mechanisms may play important roles in the molecular aetiology of NPDs.

Human genetics research lacks diversity; over 80% of genome-wide association studies (GWAS) have been conducted on individuals of European ancestry. In addition to limiting insights regarding disease mechanisms, disproportionate representation can create disparities preventing equitable implementation of personalized medicine. This systematic review provides an overview of research involving Parkinson’s disease (PD) genetics in under-represented populations (URP), and sets a baseline to measure the future impact of current efforts in those populations.We searched PubMed and EMBASE until October 2021 using search strings for “PD”, “genetics”, the main “URP”, and “lower-to-upper-middle-income countries”. Inclusion criteria were original studies, written in English, reporting genetic results on PD patients from non-European populations. Two levels of independent reviewers identified and extracted relevant information.We observed considerable imbalances in PD genetic studies among URP. Asian participants from China were described in the majority of the articles published (61%), but other populations were less well studied, for example, Blacks were represented in just 4.0% of the publications. Also, although idiopathic PD was more studied than monogenic forms of the disease, most studies analyzed a limited number of genetic variants. We identified just seven studies using a genome-wide approach published up to 2021 including URP.This review provides insight into the significant lack of population diversity in PD research highlighting the urgent need for better representation. The Global Parkinson’s Genetics Program (GP2) and similar initiatives aim to impact research in URP, and the early metrics presented here can be used to measure progress in the field of PD genetics in the future.

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). © 2021 International Parkinson and Movement Disorder Society.

The global burden of neurodegenerative disorders has increased substantially over the past 2 decades due to rising rates of population aging. Although neurodegenerative disorders differ in their clinical presentation, the underlying pathobiological processes are largely shared. Oxidative stress, among other mechanisms, is strongly implicated in neurodegenerative disorders and aging, and can potentially be targeted by antioxidative agents. Curcumin, a component of turmeric, is a compound that has received considerable attention for its therapeutic properties, and it is considered to be a powerful antioxidant. In this review, we analyzed the evidence for curcumin as an antioxidant in models of neurodegenerative disorders as well as oxido-nitrosative stress. A total of 1451 articles were found from 3 scientific literature databases (PubMed, Scopus, and Web of Science). After all exclusions, a final total of 64 articles were included in this review. The majority of the studies showed that curcumin, or derivatives thereof, were protective against oxidative and/or nitrosative stress in various cellular and animal models. Overall, curcumin protected against lipid and protein oxidation with a reduction in levels of malondialdehyde, and protein carbonyls, thiols and nitrotyrosines. Furthermore, it stimulated the activities of antioxidant enzymes such as superoxide dismutase and glutathione peroxidase. In conclusion, curcumin appears to be a promising compound for phytomedicine. However, due to some concerns about its efficacy, further targeted experiments are needed to identify its exact molecular targets and pathways responsible for its antioxidant effects.

Parkinson's disease (PD) is a movement disorder associated with severe loss of mainly dopaminergic neurons in the substantia nigra. Pathological hallmarks include Lewy bodies, and loss of neuromelanin, due to degeneration of neuromelanin-containing dopaminergic neurons. Despite being described over 200 years ago, the etiology of PD remains unknown. Here, we highlight the roles of reactive oxygen species (ROS), iron, alpha synuclein (α-syn) and neuromelanin in a toxic feedback loop culminating in neuronal death and spread of the disease. Dopaminergic neurons are particularly vulnerable due to decreased antioxidant concentration with aging, constant exposure to ROS and presence of neurotoxic compounds (e.g. ortho-quinones). ROS and iron increase each other's levels, creating a state of oxidative stress. α-Syn aggregation is influenced by ROS and iron but also increases ROS and iron via its induced mitochondrial dysfunction and ferric-reductase activity. Neuromelanin's binding affinity is affected by increased ROS and iron. Furthermore, during neuronal death, neuromelanin is degraded in the extracellular space, releasing its bound toxins. This cycle of events continues to neighboring neurons in the form of a toxic loop, causing PD pathology. The increase in ROS and iron may be an important target for therapies to disrupt this toxic loop, and therefore diets rich in certain 'nutraceuticals' may be beneficial. Turmeric is an attractive candidate, as it is known to have anti-oxidant and iron chelating properties. More studies are needed to test this theory and if validated, this would be a step towards development of lifestyle-based therapeutic modalities to complement existing PD treatments.

Introduction There have been no specific guidelines regarding which genes should be tested in the clinical setting for Parkinson's disease (PD) or parkinsonism. We evaluated the types of clinical genetic testing offered for PD as the first step of our gene curation. Methods The National Institutes of Health (NIH) Genetic Testing Registry (GTR) was queried on 12/7/2020 to identify current commercial PD genetic test offerings by clinical laboratories, internationally. Results We identified 502 unique clinical genetic tests for PD, from 28 Clinical Laboratory Improvement Amendments (CLIA)-approved clinical laboratories. These included 11 diagnostic PD panels. The panels were notable for their differences in size, ranging from 5 to 62 genes. Five genes for variant query were included in all panels (SNCA, PRKN, PINK-1, PARK7 (DJ1), and LRRK2). Notably, the addition of the VPS35 and GBA genes was variable. Panel size differences stemmed from inclusion of genes linked to atypical parkinsonism and dystonia disorders, and genes in which the link to PD causation is controversial. Conclusion There is an urgent need for expert opinion regarding which genes should be included in a commercial laboratory multi-gene panel for PD. Deborah Mascalzoni is part of Movement Society Disorder (MDS) Task Force on Recommendations for Clinical Genetic Testing in Parkinson's Disease

A decline in memory, attention, and problem-solving are often observed in normal aging; however, this decline is accelerated in aging-related disorders, such as Alzheimer’s disease. Several physiological pathways underpin cognitive decline, particularly the damage caused by oxidative stress, and subsequent neuronal death. Antioxidants can protect against this damage; however, the aging brain also becomes increasingly susceptible to dysfunctional antioxidant activity. Curcumin, a plant-based polyphenol, is known to scavenge free radicals and promote antioxidant activity. This chapter gives an overview of the molecular evidence that curcumin prevents oxidative stress, cellular senescence, and death. In addition, curcumin’s role in protection against memory impairment as evidenced by brain imaging studies is reviewed. Although there are limited published clinical trials, there is preliminary evidence for curcumin improving memory and decreasing amyloid-β plaque accumulation. Consequently, curcumin has potential as a therapy in aging and aging-related disorders and further studies on its properties are warranted.

Parkinson’s disease (PD) is a neurodegenerative disorder exhibiting Mendelian inheritance in some families. Next-generation sequencing approaches, including whole exome sequencing (WES), have revolutionized the field of Mendelian disorders and have identified a number of PD genes. We recruited a South African family with autosomal dominant PD and used WES to identify a possible pathogenic mutation. After filtration and prioritization, we found five potential causative variants inCFAP65,RTF1,NRXN2,TEP1andCCNF. The variant inNRXN2was selected for further analysis based on consistent prediction of deleteriousness across computational tools, not being present in unaffected family members, ethnic-matched controls or public databases, and its expression in the substantia nigra. A protein model for NRNX2 was created which provided a three-dimensional (3D) structure that satisfied qualitative mean and global model quality assessment scores. Trajectory analysis showed destabilizing effects of the variant on protein structure, indicated by high flexibility of the LNS-6 domain adopting an extended conformation. We also found that the known substrate N-acetyl-D-glucosamine (NAG) contributed to restoration of the structural stability of mutant NRXN2. IfNRXN2is indeed found to be the causal gene, this could reveal a new mechanism for the pathobiology of PD.

The Nigerian Parkinson Disease registry is the first published national Parkinson disease registry in sub-Saharan Africa. Though the clinical data and number of participants are currently limited in comparison with European, North American and Asian equivalents, this registry represents a valuable resource for the field.

Mitochondria are critical for cellular survival, and for their proper functioning, translocation of ∼1500 proteins across the mitochondrial membranes is required. The translocase of the outer (TOMM) and inner mitochondrial membrane (TIMM) complexes are major components of this translocation machinery. Through specific processes, preproteins and other molecules are imported, translocated, and directed to specific mitochondrial compartments for their function. In this study, we review the association of subunits of these complexes with human disease. Pathogenic mutations have been identified in the TIMM8A (DDP) and DNAJC19 (TIMM14) genes and are linked to Mohr-Tranebjaerg syndrome and dilated cardiomyopathy syndrome (with and without ataxia), respectively. Polymorphisms in TOMM40 have been associated with Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease with dementia, dementia with Lewy bodies, nonpathological cognitive aging, and various cardiovascular-related traits. Furthermore, reduced protein expression levels of several complex subunits have been associated with Parkinson's disease, Meniere's disease, and cardiovascular disorders. However, increased mRNA and protein levels of complex subunits are found in cancers. This review highlights the importance of the mitochondrial import machinery in human disease and stresses the need for further studies. Ultimately, this knowledge may prove to be critical for the development of therapeutic modalities for these conditions.

CITATION: Bardien-Kruger, S. & Muller-Nedebock, A. 2020. The role of genetics in racial categorisation of humans, in Jansen, J. & Walters, C. (eds). 2020. Fault lines : a primer on race, science and society. Stellenbosch: SUN PReSS, doi:10.18820/9781928480495/01.

Background The genetic bases of PD in sub-Saharan African (SSA) populations remain poorly characterized, and analysis of SSA families with PD might lead to the discovery of novel disease-related genes. Objectives To investigate the clinical features and identify the disease-causing gene in a black South African family with 3 members affected by juvenile-onset parkinsonism and intellectual disability. Methods Clinical evaluation, neuroimaging studies, whole-exome sequencing, homozygosity mapping, two-point linkage analysis, and Sanger sequencing of candidate variants. Result A homozygous 28-nucleotide frameshift deletion in the PTRHD1 coding region was identified in the 3 affected family members and linked to the disease with genome-wide significant evidence. PTRHD1 was recently nominated as the disease-causing gene in two Iranian families, each containing 2 siblings with similar phenotypes and homozygous missense mutations. Conclusion Together with the previous reports, we provide conclusive evidence that loss-of-function mutations in PTRHD1 cause autosomal-recessive juvenile parkinsonism and intellectual disability. © 2018 International Parkinson and Movement Disorder Society.

The Southern African Human Genome Programme is a national initiative that aspires to unlock the unique genetic character of southern African populations for a better understanding of human genetic diversity. In this pilot study the Southern African Human Genome Programme characterizes the genomes of 24 individuals (8 Coloured and 16 black southeastern Bantu-speakers) using deep whole-genome sequencing. A total of ~16 million unique variants are identified. Despite the shallow time depth since divergence between the two main southeastern Bantu-speaking groups (Nguni and Sotho-Tswana), principal component analysis and structure analysis reveal significant (p, African populations show a high level of genetic diversity and extensive regional admixture. Here, the authors sequence the whole genomes of 24 South African individuals of different ethnolinguistic origin and find substantive genomic divergence between two southeastern Bantu-speaking groups.

The loss of ventral striatal dopaminergic neurons in Parkinson's disease (PD) predicts an impact on the reward system. The ventrostriatal system is involved in motivational processing and its dysfunction may be related to non-motor symptoms such as depression and apathy. We previously documented that patients with PD had blunted Blood Oxygen Level Dependent functional magnetic resonance imaging (BOLD fMRI) reward task related activity during both reward anticipation (i.e., in the ventral striatum) and reward outcome (i.e., in the orbitofrontal cortex). Evidence for the modulation of brain function by dopaminergic genes in PD is limited. Genes implicated in dopamine transmission, such as the dopamine transporter gene (DAT1) may influence the clinical heterogeneity seen in PD, including reward processing. This study therefore sought to determine whether genetic differences in the DAT gene are associated with brain activity associated with response to reward in PD patients and controls. A sample of PD cases on treatment (n = 15) and non-PD controls (n = 30) from an ethnic group unique to South Africa were genotyped. We found a three-way interaction between GENOTYPE × BOLD fMRI REWARD × DIAGNOSIS [F (1, 40) = 4.666, p = 0.037, partial η2 = 0.104]. PD patients with the DAT1 homozygous 10/10 repeat genotype showed a relative decrease in orbitofrontal cortex reward outcome related activity compared to the patient group who did not have this repeat. PD patients with other genotypes showed an expected increase in orbitofrontal cortex reward outcome related activity compared to controls. Given the small sample size of the PD group with the 10/10 repeat, these results should be considered preliminary. Nevertheless, these preliminary findings highlight the potential modulation of dopamine transporter polymorphisms on orbitofrontal reward system activity in PD and highlight the need for further studies.

Sequence variants in glucocerebrosidase (GBA) are a major genetic risk factor for Parkinson's disease (PD), and display ethnic-dependent frequencies, for example, variants such as p.N370S and 84insGG are common in Ashkenazi Jewish patients. Notably, there are limited studies on black patients from the African continent; hence, we conducted a study on 30 South African black PD patients. All 11 exons of GBA were screened using a nested PCR approach to avoid pseudogene contamination. We identified previously described Gaucher's disease–associated variants, p.R120W in one patient [age at onset (AAO) of 35 years], and p.R131L in another patient (AAO 30 years) and in her affected sibling (AAO 45 years). In addition, we found 3 previously identified [p.K(-27)R, p.T36del, and p.Q497*] and 2 novel (p.F216L and p.G478R) variants. Screening of ethnic-matched controls for the novel variants revealed that the allele frequency of p.F216L was 9.9%, whereas p.G478R was not found in the controls. Studies such as these are important and necessary to reveal the genetic architecture underlying PD in the understudied patients of African ancestry.

Parkinson's disease (PD), a progressive neurodegenerative disorder, has long been associated with mitochondrial dysfunction in both sporadic and familial forms of the disease. Mitochondria are crucial for maintaining cellular homeostasis, and their dysfunction is detrimental to dopaminergic neurons. These neurons are highly dependent on mitochondrial adenosine triphosphate (ATP) and degenerate in PD. Mitochondria contain their own genomes (mtDNA). The role of mtDNA has been investigated in PD on the premise that it encodes vital components of the ATP-generating oxidative phosphorylation (OXPHOS) complexes and accumulates somatic variation with age. However, the association between mtDNA variation and PD remains controversial. Herein, we provide an overview of previously published studies on the role of inherited as well as somatic (acquired) mtDNA changes in PD including point mutations, deletions and depletion. We outline limitations of previous investigations and the difficulties associated with studying mtDNA, which have left its role unresolved in the context of PD. Lastly, we highlight the potential for further research in this field and provide suggestions for future studies. Overall, the mitochondrial genome is indispensable for proper cellular function and its contribution to PD requires further, more extensive investigation.

Parkinson's disease (PD) affects 1–2% of individuals above 60 years amounting to over 7 million people worldwide. Thus, PD has become an important contributor to the neurological disease burden. Nigeria is the most populous country in Africa, and alarmingly, approximately 5.25 million Nigerians are above 65 years and are therefore at risk for developing PD. We carried out a critical review of published literature on PD in Nigeria to summarize the findings and to evaluate gaps in knowledge. Seven electronic databases were searched for studies published in English before 18th July 2018. Search terms were [”Parkinson's disease” OR “Parkinson disease” OR “parkinsonian disorders” OR “Parkinsonism”] AND “Nigeria”. A total of 44 articles (including eight reviews) published since 1969 were identified and reviewed. Amongst the original research articles, most (23) were on PD symptoms or prevalence. There were only two studies on genetics and two on environmental factors. The estimated crude prevalence of PD in Nigeria was lower (10–249/100 000) compared to studies published in Europe (65.6–12 500/100 000). Our findings suggest that PD is under-diagnosed in Nigeria. Possible environmental risk factors identified include blacksmithing and well-water contaminated with trace metals. Given the rising numbers of the ageing population in Nigeria, more studies to evaluate the prevalence and causes of PD in this country are urgently needed. To this end, more funding, resources and a workforce of well-trained neurologists and scientists are essential to manage the impending health burden of PD and related disorders in this country.

The genetic bases of PD in sub-Saharan African (SSA) populations remain poorly characterized, and analysis of SSA families with PD might lead to the discovery of novel disease-related genes.To investigate the clinical features and identify the disease-causing gene in a black South African family with 3 members affected by juvenile-onset parkinsonism and intellectual disability.Clinical evaluation, neuroimaging studies, whole-exome sequencing, homozygosity mapping, two-point linkage analysis, and Sanger sequencing of candidate variants.A homozygous 28-nucleotide frameshift deletion in the PTRHD1 coding region was identified in the 3 affected family members and linked to the disease with genome-wide significant evidence. PTRHD1 was recently nominated as the disease-causing gene in two Iranian families, each containing 2 siblings with similar phenotypes and homozygous missense mutations.Together with the previous reports, we provide conclusive evidence that loss-of-function mutations in PTRHD1 cause autosomal-recessive juvenile parkinsonism and intellectual disability. © 2018 International Parkinson and Movement Disorder Society.

A wide range of neurodegenerative diseases (NDs), including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and prion diseases, share common mechanisms such as neuronal loss, apoptosis, mitochondrial dysfunction, oxidative stress, and inflammation. Intervention strategies using plant-derived bioactive compounds have been offered as a form of treatment for these debilitating conditions, as there are currently no remedies to prevent, reverse, or halt the progression of neuronal loss. Rutin, a glycoside of the flavonoid quercetin, is found in many plants and fruits, especially buckwheat, apricots, cherries, grapes, grapefruit, plums, and oranges. Pharmacological studies have reported the beneficial effects of rutin in many disease conditions, and its therapeutic potential in several models of NDs has created considerable excitement. Here, we have summarized the current knowledge on the neuroprotective mechanisms of rutin in various experimental models of NDs. The mechanisms of action reviewed in this article include reduction of proinflammatory cytokines, improved antioxidant enzyme activities, activation of the mitogen-activated protein kinase cascade, downregulation of mRNA expression of PD-linked and proapoptotic genes, upregulation of the ion transport and antiapoptotic genes, and restoration of the activities of mitochondrial complex enzymes. Taken together, these findings suggest that rutin may be a promising neuroprotective compound for the treatment of NDs.

Parkinson's disease (PD) is characterised by the loss of dopaminergic neurons in the midbrain. Autosomal recessive, early-onset cases of PD are predominantly caused by mutations in the parkin, PINK1 and DJ-1 genes. Animal and cellular models have verified a direct link between parkin and PINK1, whereby PINK1 phosphorylates and activates parkin at the outer mitochondrial membrane, resulting in removal of dysfunctional mitochondria via mitophagy. Despite the overwhelming evidence for this interaction, few studies have been able to identify a link for DJ-1 with parkin or PINK1. The aim of this review is to summarise the functions of these three proteins, and to analyse the existing evidence for direct and indirect interactions between them. DJ-1 is able to rescue the phenotype of PINK1-knockout Drosophila models, but not of parkin-knockouts, suggesting that DJ-1 may act in a parallel pathway to that of the PINK1/parkin pathway. To further elucidate a commonality between these three proteins, bioinformatics analysis established that Miro (RHOT1) interacts with parkin and PINK1, and HSPA4 interacts with all three proteins. Furthermore, 30 transcription factors were found to be common amongst all three proteins, with many of them being involved in transcriptional regulation. Interestingly, expression of these proteins and their associated transcription factors are found to be significantly down-regulated in PD patients compared to healthy controls. In summary, this review provides insight into common pathways linking three PD-causing genes and highlights some key questions, the answers to which may provide critical insight into the disease process.