The C291R Tau variant forms different types of protofibrils

Mutations in the MAPT gene can lead to disease-associated variants of tau. However, the pathological mechanisms behind these genetic tauopathies are poorly understood. Here, we characterized the aggregation stages and conformational changes of tau C291R, a recently described MAPT mutation with potential pathogenic functions. The C291R variant of the tau four-repeat domain (tau-K18; a functional fragment with increased aggregation propensity compared with the full-length protein), aggregated into a mix of granular oligomers, amorphous and annular pore-like aggregates, in native-state and heparin-treated reactions as observed using atomic force microscopy (AFM) and negative-stained electron microscopy. On extended incubation in the native-state, tau-K18 C291R oligomers, unlike wild type (WT) tau-K18, aggregated to form protofibrils of four different phenotypes: (1) spherical annular; (2) spherical annular encapsulating granular oligomers; (3) ring-like annular but non-spherical; and (4) linear protofibrils. The ring-like tau-K18 C291R aggregates shared key properties of annular protofibrils previously described for other amyloidogenic proteins, in addition to two unique features: irregular/non-spherical-shaped annular protofibrils, and spherical protofibrils encapsulating granular oligomers. Tau-K18 C291R monomers had a circular dichroism (CD) peak at ~210 nm compared with ~199 nm for tau-K18 WT. These data suggest mutation-enhanced β-sheet propensity. Together, we describe the characterization of tau-K18 C291R, the first genetic mutation substituting a cysteine residue. The aggregation mechanism of tau-K18 C291R appears to involve β-sheet-rich granular oligomers which rearrange to form unique protofibrillar structures

Neuroscience-related research in Ghana : a systematic evaluation of direction and capacity

Neurological and neuropsychiatric diseases account for considerable healthcare, economic and social burdens in Ghana. In order to effectively address these burdens, appropriately-trained scientists who conduct high-impact neuroscience research will be needed. Additionally, research directions should be aligned with national research priorities. However, to provide information about current neuroscience research productivity and direction, the existing capacity and focus need to be identified. This would allow opportunities for collaborative research and training to be properly explored and developmental interventions to be better targeted. In this study, we sought to evaluate the existing capacity and direction of neuroscience-related research in Ghana. To do this, we examined publications reporting research investigations authored by scientists affiliated with Ghanaian institutions in specific areas of neuroscience over the last two decades (1995–2015). 127 articles that met our inclusion criteria were systematically evaluated in terms of research foci, annual publication trends and author affiliations. The most activelyresearched areas identified include neurocognitive impairments in non-nervous system disorders, depression and suicide, epilepsy and seizures, neurological impact of substance misuse, and neurological disorders. These studies were mostly hospital and community-based surveys. About 60 % of these articles were published in the last seven years, suggesting a recent increase in research productivity. However, data on experimental and clinical research outcomes were particularly lacking. We suggest that future investigations should focus on the following specific areas where information was lacking: large-scale disease epidemiology, effectiveness of diagnostic platforms and therapeutic treatments, and the genetic, genomic and molecular bases of diseases

Neurogenomics : challenges and opportunities for Ghana

The application of genomic tools and technologies has shown the potential to help improve healthcare and our understanding of disease mechanisms. While genomic tools are increasingly being applied to research on infectious diseases, malaria and neglected tropical diseases in Africa, an area that has seen little application of genomic approaches on this continent is neuroscience. In this article, we examined the prospects of developing neurogenomics research and its clinical use in Ghana, one of the African countries actively involved in genomics research. We noted that established international research funding sources and foundations in genomic research such as H3ABioNet nodes established at a couple of research centres in Ghana provide excellent platforms for extending the usage of genomic tools and techniques to neuroscience-related research areas. However, existing challenges such as the (i) lack of degree programmes in neuroscience, genomics and bioinformatics; (ii) low availability of infrastructure and appropriately-trained scientists; and (iii) lack of local research funding opportunities, need to be addressed. To promote and safeguard the long-term sustainability of neurogenomics research in the country, the impact of the existing challenges and possible ways of addressing them have been discussed

Potential role of metabolomics in the improvement of research on traditional African medicine

The global market for herbal medicine is growing steadily. The usage of herbal medicine is particularly common in many parts of Africa; the World Health Organization estimates that approximately 80% of Africans rely on traditional African medicines (TAMs) for treating various diseases. TAMs hold promise in preventive treatment, early disease intervention and personalized medicine. However, clinical integration of TAMs is restricted due to limited information concerning their characterization. Presently, many studies on TAMs utilize a reductionist approach, making it extremely difficult to understand the holistic modifying effects that these therapeutic agents may have on biological systems. Fortunately, emerging technologies such as metabolomics platforms adopt a ‘top-down’ strategy that permits a holistic evaluation of the components, metabolic pathways and biomarkers modified by TAMs, which can aid in addressing common concerns over safety and toxicity, while also ensuring that quality control standards are met. Metabolomics approaches may also be beneficial for advancing our understanding of the efficacy and mechanism of action of TAMs, and may contribute to the advancement of research and drug discovery, early diagnosis, preventive treatment and TAMs-driven personalized medicine in Africa. This review also considers the main challenges that may hinder the adoption and integration of metabolomics approaches in research on TAMs in Africa and suggests possible solutions

Neurogenomics: An opportunity to integrate neuroscience, genomics and bioinformatics research in Africa

AbstractModern genomic approaches have made enormous contributions to improving our understanding of the function, development and evolution of the nervous system, and the diversity within and between species. However, most of these research advances have been recorded in countries with advanced scientific resources and funding support systems. On the contrary, little is known about, for example, the possible interplay between different genes, non-coding elements and environmental factors in modulating neurological diseases among populations in low-income countries, including many African countries. The unique ancestry of African populations suggests that improved inclusion of these populations in neuroscience-related genomic studies would significantly help to identify novel factors that might shape the future of neuroscience research and neurological healthcare. This perspective is strongly supported by the recent identification that diseased individuals and their kindred from specific sub-Saharan African populations lack common neurological disease-associated genetic mutations. This indicates that there may be population-specific causes of neurological diseases, necessitating further investigations into the contribution of additional, presently-unknown genomic factors. Here, we discuss how the development of neurogenomics research in Africa would help to elucidate disease-related genomic variants, and also provide a good basis to develop more effective therapies. Furthermore, neurogenomics would harness African scientists' expertise in neuroscience, genomics and bioinformatics to extend our understanding of the neural basis of behaviour, development and evolution

Disregard of neurological impairments associated with neglected tropical diseases in Africa

Neglected tropical diseases (NTDs) affect people in the bottom billion poorest in the world. These diseases are concentrated in rural areas, conflict zones and urban slums in Africa and other tropical areas. While the World Health Organization recognizes seventeen priority NTDs, the list of conditions present in Africa and elsewhere that are eligible to be classified as NTDs is much longer. Although NTDs are generally marginalized, their associated neurological burden has been almost completely disregarded. However, reports indicate that trichuriasis, schistosomiasis and hookworm infection, among others, cause impairments in memory and cognition, negatively affecting school attendance rates and educational performance particularly among children, as well as agricultural productivity among adults. Consequently, the neurological impairments have substantial influence on education and economic productivity, thus aggravating and perpetuating poverty in affected societies. However, inadequate research, policy and public health attention has been paid to the neurological burdens associated with NTDs. In order to appropriately address these burdens, we recommend the development of policy interventions that focus on the following areas: (i) the introduction of training programs to develop the capacity of scientists and clinicians in research, diagnostic and treatment approaches (ii) the establishment of competitive research grant schemes to fund cutting-edge research into these neurological impairments, and (iii) the development of public health interventions to improve community awareness of the NTD-associated neurological problems, possibly enhancing disease prevention and expediting treatment

Widening participation would be key in enhancing bioinformatics and genomics research in Africa

Bioinformatics and genome science (BGS) are gradually gaining roots in Africa, contributing to studies that are leading to improved understanding of health, disease, agriculture and food security. While a few African countries have established foundations for research and training in these areas, BGS appear to be limited to only a few institutions in specific African countries. However, improving the disciplines in Africa will require pragmatic efforts to expand training and research partnerships to scientists in yet-unreached institutions. Here, we discuss the need to expand BGS programmes in Africa, and propose mechanisms to do so

Building sustainable neuroscience capacity in Africa : the role of non-profit organisations

While advances in neuroscience are helping to improve many aspects of human life, inequalities exist in this field between Africa and more scientifically-advanced continents. Many African countries lack the infrastructure and appropriately-trained scientists for neuroscience education and research. Addressing these challenges would require the development of innovative approaches to help improve scientific competence for neuroscience across the continent. In recent years, science-based non-profit organisations (NPOs) have been supporting the African neuroscience community to build state-of-the-art scientific capacity for sustainable education and research. Some of these contributions have included: the establishment of training courses and workshops to introduce African scientists to powerful-yet-cost-effective experimental model systems; research infrastructural support and assistance to establish research institutes. Other contributions have come in the form of the promotion of scientific networking, public engagement and advocacy for improved neuroscience funding. Here, we discuss the contributions of NPOs to the development of neuroscience in Africa

Distinct conformations, aggregation and neuronal internalisation of different tau strains

A shared property of several neurodegenerative diseases is the neuronal accumulation of aggregated tau protein. These include Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Many studies have suggested that aggregated tau accumulation in AD brains involves: (i) internalisation of extracellular tau (aggregated or not) into neurons; (ii) induction of endogenous tau aggregation by the internalised tau; and (iii) secretion of part or whole of this aggregated tau complex. This complex then initiates a new cycle of internalisation, aggregation and secretion. While this AD mechanism has strong evidential support, it is unclear if it applies to FTD. It was therefore investigated if and how two FTD-associated tau mutations, V337M and N279K, affect in vitro wild type (WT) tau aggregation and conformation, and studied the cell biological effects of their respective extracellular oligomers. A library of 43 plasmids for expressing full-length and truncated tau and their FTD variants were created, in conjunction with the establishment of a new high-yield tau purification method. Consequently, in vitro biochemical assays showed that the FTD variants distinctively altered the immunological reactivity, the stages of aggregation, and the structural phenotypes of aggregated WT tau four-repeat domain, K18. Internalisation of WT and FTD tau K18 extracellular oligomers was significantly different in human neuroblastoma cells and human stem-cell derived neurons. Internalisation seemed to occur by endocytosis, and the internalised oligomers localised to the nucleus and cytoplasm of human neuroblastoma cells and the soma and neurites of stem cell-derived neurons. Moreover, internalised oligomers co-localised with endogenous tau and the nuclear protein nucleolin, without inducing cell death. These findings provide new perspectives to the cell-to-cell propagation theory of aggregated tau, by demonstrating that cellular internalisation of tau variants may be tightly regulated by the given protein’s folding and aggregation characteristics. This may help to explain several enigmatic aspects of the molecular pathogenesis found in different tauopathies