Seminars

Shimon Sakaguchi, Mary E. Brunkow and Fred Ramsdell explain how peripheral immune tolerance prevents the immune system from attacking the body. Sakaguchi follows the identification of regulatory T cells, the CD25 marker, and the relationship between central tolerance and active suppression of self-reactive cells. He considers how changing regulatory T-cell activity could support cancer treatment and transplantation. Brunkow describes genetic investigation of scurfy mice, identification of FOXP3, and the connection between mutations in this gene and human IPEX syndrome. The work establishes a molecular basis for the development and function of regulatory T cells. Ramsdell traces the move from these basic discoveries toward therapeutic strategies, including engineering a patient’s regulatory T cells to target inflammation in rheumatoid arthritis. He discusses early clinical investigation and the ambition of restoring immune balance; these approaches are presented as developing treatments rather than established cures.

The presentation will provide an overview of the expanding role of genetic factors in epilepsy. It will delve into the fundamentals of this field and elucidate how digital tools and resources can aid in the re-evaluation of genetic test results. In the initial segment of the presentation, Dr. Lal will examine the advancements made over the past two decades regarding the genetic architecture of various epilepsy types. Additionally, he will present research studies in which he has actively participated, offering concrete examples. Subsequently, during the second part of the talk, Dr. Lal will share the ongoing research projects that focus on epilepsy genetics, bioinformatics, and health record data science.

Ophthalmology is ideally placed to benefit from recent advances in artificial intelligence. It is a highly image-based specialty and provides unique access to the microvascular circulation and the central nervous system. This talk will demonstrate diverse applications of machine learning and deep learning techniques in ophthalmology, including in age-related macular degeneration (AMD), the leading cause of blindness in industrialized countries, and cataract, the leading cause of blindness worldwide. This will include deep learning approaches to automated diagnosis, quantitative severity classification, and prognostic prediction of disease progression, both from images alone and accompanied by demographic and genetic information. The approaches discussed will include deep feature extraction, label transfer, and multi-modal, multi-task training. Cluster analysis, an unsupervised machine learning approach to data classification, will be demonstrated by its application to geographic atrophy in AMD, including exploration of genotype-phenotype relationships. Finally, mediation analysis will be discussed, with the aim of dissecting complex relationships between AMD disease features, genotype, and progression.

During life, a variety of specialized cells arise to grant the right and timely corrected functions of tissues and organs. Regulation of chromatin in defining specialized genomic regions (e.g. enhancers) plays a key role in developmental transitions from progenitors into cell lineages. These enhancers, properly topologically positioned in 3D space, ultimately guide the transcriptional programs. It is becoming clear that several pathologies converge in differential enhancer usage with respect to physiological situations. However, why some regulatory regions are physiologically preferred, while some others can emerge in certain conditions, including other fate decisions or diseases, remains obscure. Schinzel-Giedion syndrome (SGS) is a rare disease with symptoms such as severe developmental delay, congenital malformations, progressive brain atrophy, intractable seizures, and infantile death. SGS is caused by mutations in the SETBP1 gene that results in its accumulation further leading to the downstream accumulation of SET. The oncoprotein SET has been found as part of the histone chaperone complex INHAT that blocks the activity of histone acetyltransferases suggesting that SGS may (i) represent a natural model of alternative chromatin regulation and (ii) offer chances to study downstream (mal)adaptive mechanisms. I will present our work on the characterization of SGS in appropriate experimental models including iPSC-derived cultures and mouse.

Focal Cortical Dysplasia (FCD) is the most common focal cortical malformation leading to intractable childhood focal epilepsy. In recent years, we and others have shown that FCD type II is caused by mosaic mutations in genes within the PI3K-AKT-mTOR-signaling pathway. Hyperactivation of the mTOR pathway accounts for neuropathological abnormalities and seizure occurrence in FCD. We further showed from human surgical FCDII tissue that epileptiform activity correlates with the density of mutated dysmorphic neurons, supporting their pro-epileptogenic role. The level of mosaicism, as defined by variant allele frequency (VAF) is thought to correlate with the size and regional brain distribution of the lesion such that when a somatic mutation occurs early during the cortical development, the dysplastic area is smaller than if it occurs later. Novel approaches based on the detection of cell-free DNA from the CSF and from trace tissue adherent to SEEG electrodes promise future opportunities for genetic testing during the presurgical evaluation of refractory epilepsy patients or in those that are not eligible for surgery. In utero-based electroporation mouse models allow to express somatic mutation during neurodevelopment and recapitulate most neuropathological and clinical features of FCDII, establishing relevant preclinical mouse models for developing precision medicine strategies.

Genome-wide association studies and functional genomics studies have linked specific cell types, genes, and pathways to Alzheimer’s disease (AD) risk. In particular, AD risk alleles primarily affect the abundance or structure, and thus the activity, of genes expressed in macrophages, strongly implicating microglia (the brain-resident macrophages) in the etiology of AD. These genes converge on pathways (endocytosis/phagocytosis, cholesterol metabolism, and immune response) with critical roles in core macrophage functions such as efferocytosis. Here, we review these pathways, highlighting relevant genes identified in the latest AD genetics and genomics studies, and describe how they may contribute to AD pathogenesis. Investigating the functional impact of AD-associated variants and genes in microglia is essential for elucidating disease risk mechanisms and developing effective therapeutic approaches." https://doi.org/10.1016/j.neuron.2022.10.015

Parkinson’s Disease (PD), the most common neurodegenerative movement disorder, is based on a complex interplay between genetic predispositions, aging processes, and environmental influences. In order to better understand the gene-environment axis in PD, we pursue a multi-omics approach to comprehensively interrogate genome-wide changes in histone modifications, DNA methylation, and hydroxymethylation, accompanied by transcriptomic profiling in cell and animal models of PD as well as large patient cohorts. Furthermore, we assess the plasticity of epigenomic modifications under influence of environmental factors using longitudinal cohorts of sporadic PD cases as well as mouse models exposed to specific environmental factors. Here, we present gene expression changes in PD mouse models in context of aging as well as environmental enrichment and high-fat diet.

The origins, mechanisms and consequences of epilepsy in the developing brain are incompletely understood. Many developmental epilepsies have a genetic basis and their mechanisms stem from deficits in the function of one or numerous genes. Others, such as those that follow prolonged febrile seizures or severe birth asphyxia in a ‘normal’ brain may depend on the interaction of the insult with the rapidly evolving brain cells and circuits. Yet, how early-life insults may provoke epilepsy is unclear, and requires multiple levels of analysis: behavior, circuits, cells [neurons, glia] and molecules. Here we discuss developmental epileptogenesis, addressing some of its special features: the epilepsy phenotype, the effects insults on the maturation of brain circuits, the role of neuron-glia-neuron communication in cellular and circuit refinement, and how transient epileptogenic insults provoke enduring changes in the structure, connectivity and function of salient neuronal populations. We will highlight resolved questions- and the many unresolved issues that require tackling in 2022 and beyond.