Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy

AbstractDevelopmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.</jats:p

The holy grail of longevity research

10.7554/eLife.85001ELIFE1

Total Recall: Lateral Habenula and Psychedelics in the Study of Depression and Comorbid Brain Disorders

Depression impacts the lives and daily activities of millions globally. Research into the neurobiology of lateral habenula circuitry and the use of psychedelics for treating depressive states has emerged in the last decade as new directions to devise interventional strategies and therapies. Several clinical trials using deep brain stimulation of the habenula, or using ketamine, and psychedelics that target the serotonergic system such as psilocybin are also underway. The promising early results in these fields require cautious optimism as further evidence from experiments conducted in animal systems in ecologically relevant settings, and a larger number of human studies with improved spatiotemporal neuroimaging, accumulates. Designing optimal methods of intervention will also be aided by an improvement in our understanding of the common genetic and molecular factors underlying disorders comorbid with depression, as well as the characterization of psychedelic-induced changes at a molecular level. Advances in the use of cerebral organoids offers a new approach for rapid progress towards these goals. Here, we review developments in these fast-moving areas of research and discuss potential future directions

Modeling Alzheimer’s and Other Age Related Human Diseases in Embryonic Systems

Modeling human disease in animals is an important strategy to discover potential methods of intervention. We suggest that there is much to be gained by employing a multi-model approach that takes advantage of different animal systems used in the laboratory simultaneously. We use the example of modeling Alzheimer’s disease in Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio to illustrate how such an approach can be employed to investigate the pathophysiology of the disease

Why behavioral neuroscience still needs diversity? : A curious case of a persistent need

In the past few decades, a substantial portion of neuroscience research has moved from studies conducted across a spectrum of animals to reliance on a few species. While this undoubtedly promotes consistency, in-depth analysis, and a better claim to unraveling molecular mechanisms, investing heavily in a subset of species also restricts the type of questions that can be asked, and impacts the generalizability of findings. A conspicuous body of literature has long advocated the need to expand the diversity of animal systems used in neuroscience research. Part of this need is utilitarian with respect to translation, but the remaining is the knowledge that historically, a diverse set of species were instrumental in obtaining transformative understanding. We argue that diversifying matters also because the current approach limits the scope of what can be discovered. Technological advancements are already bridging several practical gaps separating these two worlds. What remains is a wholehearted embrace by the community that has benefitted from past history. We suggest the time for it is now.Ministry of Education (MOE)Accepted versionASM was supported via Yale-NUS College grants R-607-265-225-121, FL via the United States-Israel Binational Sciences Foundation(2015161), AV via Human Frontier Science Program (RGP0062/2018) and by the Ministry of Education, Singapore, under its MOE AcRF Tier 3Award MOE2017-T3-1-002. and ST via a Presidential Postdoctoral Fellowship from Nanyang Technological University (NTU) M408080000

HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring

The body plan of animals is laid out by an evolutionary-conserved HOX code which is colinearly transcribed after zygotic genome activation (ZGA). Here we report that SMCHD1, a chromatin-modifying enzyme needed for X-inactivation in mammals, is maternally required for timely HOX expression. Using zebrafish and mouse Smchd1 knockout animals, we demonstrate that Smchd1 haplo-insufficiency brings about precocious and ectopic HOX transcription during oogenesis and embryogenesis. Unexpectedly, wild-type offspring born to heterozygous knockout zebrafish smchd1 mothers exhibited patent vertebrate patterning defects. The loss of maternal Smchd1 was accompanied by HOX epi-mutations driven by aberrant DNA methylation. We further show that this regulation is mediated by Lrif1, a direct interacting partner of Smchd1, whose knockout in zebrafish phenocopies that of Smchd1. Rather than being a short-lived maternal effect, HOX mis-regulation is stably inherited through cell divisions and persists in cultured fibroblasts derived from FSHD2 patients haploinsufficient for SMCHD1. We conclude that maternal SMCHD1/LRIF1 sets up an epigenetic state in the HOX loci that can only be reset in the germline. Such an unusual inter-generational inheritance, whereby a phenotype can be one generation removed from its genotype, casts a new light on how unresolved Mendelian diseases may be interpreted

A Neurexin2aa deficiency results in axon pathfinding defects and increased anxiety in zebrafish

10.1093/hmg/ddaa260HUMAN MOLECULAR GENETICS29233765-378