The ISN Neuroscience School, Ondo 2024, Gene–environment interactions in neurological disorders: a contemporary update Open Access

The International Society for Neurochemistry (ISN) is a society that promotes and supports the advancement of neurochemistry research and education globally. It focuses mainly on building capacity in molecular and cellular neuroscience research by exposing students and faculty members to recent and groundbreaking advances in the field. Over the years, this society has sponsored numerous scientific meetings such as this and has assembled academics (faculties and students) of various academic stages and disciplines from around the globe to partake in scientific lectures and discussions on relevant neurochemical research topics. This year's ISN School was hosted at the University of Medical Sciences, Ondo State, Nigeria, from 11–16 August 2024. The school also received additional support from the Company of Biologists.

This school was aimed at providing a robust scholarly contemporary update on the interplay between genetic and environmental factors in the pathogenesis of various neurological disorders. Recent studies have been focused on unravelling how this complex interaction can provide relevant biological insights into the aetiology, progression, and outcomes of prevalent neurological disorders including Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD) (Dunn et al., 2019; Wexler, 2004; Migliore and Coppedè, 2022). Prolonged and cumulated interactions between environmental and genetic risk factors have been shown to significantly influence disease risk, particularly in age-related neurodegenerative diseases (Pang et al., 2019). However, the intricacies involved in these interactions are yet to be fully understood although some studies have suggested that this phenomenon is associated with the impairment of cellular pathways and perturbation of neuronal processes, which consequently leads to neuronal death (Pang et al., 2019; Eid et al., 2019; Machiela and Southwell, 2020). Hence, getting a solid grasp of the mechanisms implicated in the aetiology of these neurological disorders could contribute to developing relevant interventions and personalized therapeutics. Among various experimental research models, the Caenorhabditis elegans (C. elegans), has particularly been useful in modelling various human neurological diseases. This model has been employed in studying the cellular and molecular mechanisms underlying the pathogenesis of some neurodegenerative disorders (Fig. 1). The C. elegans has been leveraged to study relevant topics in molecular biology (Haroon et al., 2018), toxicology (Gubert et al., 2018; Ijomone et al., 2024), neuroscience (Denzel et al., 2019) and genetics (Gao et al., 2018). Its advantage over other model organisms includes its short life span and simple morphology and over 70% homology to human genes, as well as a completely mapped neural network. In addition, it is easy to grow and maintain and can be genetically manipulated without stress. The Drosophila melanogaster (D. melanogaster) is another model organism that has proven valuable in studying various neurodegenerative diseases (Huang et al., 2020; Aryal and Lee, 2019). About 75% of all human disease genes have Drosophila homologues (Bilen and Bonini, 2005), hence its applicability in studying neurodegenerative diseases like AD and PD.

In this Meeting Review, we provide an overview of the lectures taken by international and national faculties, interactive forums, as well as practical sessions. The hands-on practical sessions incorporated both basic and advanced research techniques involving the use of the rodent and C. elegans models. These sessions were aimed at equipping participants with valuable knowledge and skillsets needed to improve their research output in various areas relevant to neuroscience.

The ISN School Neuroscience School brought together a diverse cohort of participants from different geopolitical regions in Nigeria and across Africa. The meeting adopted a hybrid format with some participants joining in person while others joined virtually. In-person attendees comprised of 33 students, 29 of whom were Nigerians from the six geopolitical zones of the country, and five participants attending from other African countries including Cameroun, South Africa, Rwanda, and Uganda. The in-person attendance had an even gender distribution comprising 16 male and 17 female participants across different academic stages including early career researchers, postdoctoral fellows, PhD, and MSc students (Fig. 2) from diverse academic disciplines such as biochemistry, anatomy, physiology, medicine, and pharmacology. Having participants from various academic disciplines enhanced the overall learning experience, leading to insightful interactive sessions and discussions as students were able to provide unique insights and perspectives from diverse research fields. In addition, 59 participants (36 males and 23 females) were selected to participate virtually. Participants in this category included graduate students (MSc and PhD), postdoctoral fellows and early career researchers (Fig. 2).

A major highlight of the ISN Neuroscience School was the series of lectures delivered by distinguished international and local speakers attending physically and virtually. Most of the lectures evolved around the use of the C. elegans worm model for studying interactions between environmental and genetic components and also its applicability in neuroscience, neuropharmacology, toxicology and genetic research (Fig. 3). However, later during the school, a fresh perspective was introduced by Professors Amos Abolaji and Monica Paoliello. Professor Amos walked the participants through the use of D. melanogaster for studies on neurodegenerative diseases. Professor Monica Paoliello discussed major concepts and correct practices involved in reviewing literature for research.

The keynote lecture was delivered by Professor Michael Aschner, a renowned researcher from the Albert Einstein College of Medicine, USA, discussing some novel approaches to unravelling simultaneous contributions of genes and environment in brain diseases. He commenced by briefly overviewing the C. elegans animal model, laying emphasis on its advantages as an experimental model for research in diverse fields not limited to toxicology, pharmacology, neuroscience, and genetics. His lecture focused on elucidating mechanism through which manganese (Mn) enters the brain which is mostly via the Divalent Metal Tansporter-1 (DMT-1), resulting to neurotoxicity and pathogenesis of some neurological disorders like PD; smf-1 and smf-3 are relevant homologues for human DMT-1 in C. elegans. In his second lecture, he focused on the role of metal transporters in neurological disorders. He discussed some implications of heavy metal exposure and accumulation, as well as the interactions between metals like iron (Fe), Mn and their transporters in the brain while connecting it to the aetiology of restless leg syndrome (RLS) to metal imbalance. He also identified a gene called BTBD9, which helps regulate Fe levels in the brain. He concluded his lecture by showing that loss of function in this gene is linked with greater susceptibility to Mn-induced oxidative stress, mitochondrial dysfunction, and decreased dopamine levels (Gunter et al., 2013; Chen et al., 2022).

Professor Dr Julia Bornhorst from the University of Wuppertal, Germany also gave a lecture focusing on the interplay between Mn neurotoxicity and parkin/PARK2 and PINK mutations in PD. She discussed how heavy exposure to Mn contributes to the pathogenesis and progression of PD following mutations in parkin and PINK1 genes in the C. elegans. Her lecture highlighted the influence of these interactions on various parameters employed to study neurodegeneration in the C. elegans including dopamine functioning, mitochondrial dysfunction, and neuronal damage (Bornhorst et al., 2014). In addition, Mrs Comfort Ofure Okoh, a doctoral candidate with the Max Planck School of Cognition, Germany, delivered a short virtual demonstration focusing on the identification of risk variants through the use of enhancer screening tools, and how they contribute to neuropsychiatric disorders such as schizophrenia, psychosis, and epilepsy (Fig. 4b).

Professor Monica Paoliello from the Albert Einstein College of Medicine, USA, gave her lecture titled ‘Cadmium (Cd) exposure and hypertension: the role of the nervous system’. She highlighted some common sources of Cd exposure and also discussed toxicity that arises from its accumulation over time in a variety of organ systems, including the liver, kidneys, and central and peripheral nervous systems. These adverse health effects include hypertension, cardiovascular mortality, peripheral arterial disease, cancer mortality, and chronic kidney disease. She described several mechanisms that may explain the relationship between Cd exposure and altered health parameters including blood pressure, blood–brain barrier integrity, and renal functioning. Some of which were a result of predisposing factors like gender susceptibility and lifestyle choices.

Professor Félix Antunes Soares from the Federal University of Santa Maria, Brazil, delivered his lecture on modelling gene-toxicant contribution to HD using the C. elegans model. He started his lecture by highlighting reasons why we should leverage on the C. elegans animal model for neuroscience research especially for neurodegenerative diseases like HD. He highlighted some C. elegans strains that are used to study HD, many of which are available at the Caenorhabditis Genetics Center (CGC). He discussed extensively the role Diphenyl diselenide plays in protecting the C. elegans model of HD. This involves the activation of the antioxidant pathway and a decrease in protein aggregation. In addition, he showed that another substance called rutin could protect against HD through the insulin signalling pathway and autophagy activity. He concluded by highlighting future directions involving investigating the trans-generational and epigenetic implications of long-term exposure to pesticides and heavy metals in neurodegenerative diseases (Soares et al., 2017; Bicca Obetine Baptista et al., 2020; Cordeiro et al., 2020).

Dr Omamuyovwi Ijomone from the University of Medical Sciences, Ondo, discussed the impacts of metal toxicities and NRXN/NLGN mutations on neuronal perturbations in autism. His lecture commenced by identifying the burden posed by crude oil spillage and heavy metal contamination in the environment, especially in some parts of Nigeria. He further discussed various research that has studied the toxic impact of Nickel (Ni) in the rodent and C. elegans models. For instance, early-life exposure to Ni was shown to induce developmental and behavioural deficits in wild-type young adult C. elegans (Ijomone et al., 2020). The mechanism was shown to involve oxidative stress via SKN-1 (worm homologue for human Nrf2) regulation. He further described the role of Mn and Fe in modulating toxicities and neural perturbations in nrx-1/nlg-1 loss-of-function in C. elegans (unpublished data). In addition, he demonstrated neurological deficits that could arise as a result of co-exposure of heavy metals and stressful events in rodents' brains (Okeowo et al., 2024).

Dr Alexander Benedetto from Lancaster University delivered two lectures entitled ‘Gut-microbiome modulation of genetic risk factors in neurodegenerative diseases’ and ‘Gene–environment interplay in brain senescence’. The first lecture focused on the gut-brain axis and kynurenine pathway. In this lecture, he laid emphasis on the importance of studying this pathway, which is mostly because of the diversity of metabolites it produces. His second lecture provided insights on the evolution of neurodegenerative diseases, typically in relation to ageing. He identified the changes that take place in the brain as it ages, shedding light on the fate of key components like the synapses. In addition, he discussed various techniques applicable to the C. elegans model that have been developed to study brain functions (Fig. 4a). Last but not the least, Professor Amos Abolaji from the University of Ibadan, Nigeria, delivered his lecture titled ‘Assessing natural products on toxicants models of Alzheimer's and Parkinson's disease in D. melanogaster’. In this lecture, he discussed the suitability of the D. melanogaster for neurodegenerative disease studies, and why employing this model organism is critical for AD and PD research. He also discussed the roles natural products can play in rescuing chemically induced perturbations observed in these diseases. His lecture also revealed some natural products like Resveratrol that could attenuate toxicity induced in D. melanogaster.

We had 2 days of intensive practical sessions during the neuroscience school. The practical sessions were on C. elegans, rat brain dissection, rodent behavioural demonstrations and immunohistochemistry. All attendees were divided into two groups for effective learning and participation.

The participants were taught how to properly dissect the rat brain, and how to carry out a complete immunohistochemical procedure, after which they stained a hippocampal brain region using GFAP and TNF alpha as biomarkers. Various rodent behavioural assays were also introduced to the participants. These include the open field test (OFT), novel object recognition test (NORT), Y-maze, elevated zero maze (EZM), T-maze, elevated plus maze (EPM), forepaw grip, and forced swim tests. Furthermore, the participants were briefly introduced to the C. elegans experimental workflow and the various assays that could be performed using this model after which they attempted the worm synchronization procedure. In all, the practical session not only offered a good learning experience, but also provided new ideas and insights for the participants (Fig. 5).

This session was led by Professor Amos Abolaji, Dr Kingsley Iteire, Professor Felix Soares, and Dr Omamuyovwi Ijomone, and served as an avenue for faculties-to-students and student-to-student interaction and networking. Grantsmanship was discussed during this session, alongside the various challenges faced by scientists in developing countries, and how to overcome them. Ethical issues in biomedical research were also discussed (Fig. 6).

On 15 August 2024, there was a guided tour visit to La Campagne Tropicana, a stunning retreat destination situated in Ondo town (Fig. 7). This unique destination was designed with the sole purpose of showcasing and preserving African heritage, offering a deep connection to our cultural roots. The visit provided a much-needed break for the participants and faculty of the school. The hilltop location of La Campagne Tropicana not only offered a refreshing atmosphere but also gave us breathtaking panoramic views of Ondo town and its surrounding landscapes. The serene environment, combined with the rich cultural aesthetics created the perfect backdrop for relaxation and reflection. During our time there, the participants and faculty members engaged in various recreational activities, fostering friendship and relaxation. Games like table tennis, snooker and ‘shoot the basket’ were enthusiastically played, offering a fun and lively way to unwind after academic sessions.

The ISN Neuroscience School 2024 provided a contemporary update on gene–environment interactions in neurological disorders, a field that is increasingly relevant given the rising prevalence of neurodegenerative diseases. The interaction between genetic predispositions and environmental exposures, particularly in neurodegenerative diseases like PD, AD and HD, was a recurring theme throughout the event. As underscored by keynote speaker Professor Michael Aschner, understanding how genes and environmental toxicants, such as metals like Mn and Fe, contribute to neurological disorders is crucial. His discussion on the roles of metal transporters and gene mutations, like BTBD9 in RLS, highlighted the complexity of these interactions. Professor Julia Bornhorst's investigation of parkin and PINK1 mutations in PD further emphasized the molecular mechanisms through which environmental toxins exacerbate genetic vulnerabilities, leading to neuronal dysfunction. This knowledge is critical in addressing the clinical challenges posed by neurodegenerative diseases, which are multifactorial in origin. Identifying risk factors and understanding how they synergize to drive disease progression can lead to more effective interventions. Professor Felix A. Antunes Soares's research on protective compounds like diphenyl diselenide and rutin in C. elegans models of HD showcases how experimental models can help elucidate potential therapeutic targets. The Drosophila model, presented by Professor Amos Abolaji, also demonstrated its utility in investigating neurotoxic responses and testing neuroprotective natural compounds, Professor Abolaji also emphasized the possibility of looking at sexual dimorphism in the fruit fly.

Another key theme was the impact of environmental pollutants like Cd on neurological health. Professor Monica Paoliello's discussion on the link between Cd exposure and hypertension, mediated through nervous system dysfunction, emphasized the broader health impacts of environmental toxins beyond neurodegeneration. Her insights into blood–brain barrier integrity and renal functions highlighted the importance of considering systemic health outcomes when assessing environmental toxicants' effects on the brain. Metal toxicity, particularly Mn and Ni, was a central focus in discussions on neurotoxicity. Dr Ijomone's research on early life exposure to Ni and its developmental effects in C. elegans, along with his work on Mn and Fe interactions in nrx-1/nlg-1 mutations, pointed to a growing body of evidence linking metal toxicity to neurodevelopmental and neurodegenerative outcomes. His findings on co-exposure to heavy metals and stressors in rodent models echoed the idea that environmental toxicants can have chronic or long-lasting impacts on the well-being of the brain.

Emerging research topics, such as the influence of gut microbiota on neurodegeneration and gene-environment interactions in brain senescence, were presented by Dr Alexander Benedetto. These topics represent exciting frontiers in neuroscience, where interdisciplinary approaches are shedding light on previously underexplored mechanisms. The integration of microbiome research into the study of neurodegeneration provides new approaches for therapeutic interventions.

The ISN Neuroscience School, Ondo 2024 successfully provided an in-depth investigation of gene-environment interactions in neurological disorders, combining lectures by faculties, students’ presentations, practical sessions and interactive forums. The different research presented emphasized the importance of using both genetic and environmental lenses to study neurodegeneration. The insights gained from this school, particularly in the context of model organisms and metal toxicity, will undoubtedly contribute to future research directions and therapeutic strategies in neuroscience.

The participants of the ISN Neuroscience School, Ondo, express their profound gratitude to the members of the Laboratory for Experimental and Translational Neuroscience (LETNeu) at the University of Medical Sciences, Ondo (UNIMED) for organizing the programme, and the Vice-Chancellor of UNIMED, Professor Fatusi Adesegun and his management team for providing steady institutional support. Special appreciation also goes to all the faculty and instructors (Fig. 8).