HID1 as a novel disease-causing gene in early onset neurological disorders: molecular, functional and phenotypic studies

Rare neurological diseases with genetic causes are gaining relevance for child morbidity and mortality due to improvements in health care, prevention and treatment of conventional life-limiting diseases in infants. Emerging and improving high-throughput sequencing technologies constitute a key tool in determining disease-causing mutations and allow the identification of potential new disease-related genes. This way, high-temperature induced dauer 1 (HID1), a known player in large dense core vesicle (LDCV)-based peptidergic signaling in C. elegans and rodents, was identified as a novel potential disease-related gene in two patients presenting with a unique neurologic and neuroendocrine phenotype. The aim of this project was to molecularly link the detected homozygous mutation in HID1 to the presented clinical defects in patients. First, this study investigated HID1 and a CRISPR/Cas9-introduced patient-derived mutation in a human neuroendocrine cell line, which constitutes a widely accepted model system for neurological disease. Basic research on HID1 revealed that it is a Golgi-associated protein but also localizes to the cytosol, possibly to LDCV in human neuroendocrine cells. It could be proven that HID1 expression is exceptionally high in the pituitary gland and increases with neuronal differentiation, linking HID1 to neurodevelopment. Co-immunoprecipitation followed by mass spectrometry-based identification of interacting protein candidates could substantially broaden the spectrum of potential HID1 functions, linking HID1 especially to the biological processes of intracellular localization establishment, intracellular and transmembrane transport and cytoskeletal organization. Considering allocation of interactors to cellular components, HID1 appears to be prominently associated with the Golgi apparatus and related vesicles, which corresponds to the results of the localization study. Patient mutation-carrying cells and HID1 knockout cells were used to investigate molecular genotype-phenotype relations in suspected HID1-related disease. It could be demonstrated that the patient-derived HID1 mutation leads to the absence of detectable protein, resulting from degradation of the corresponding mutant HID1 mRNA via nonsense-mediated mRNA decay (NMD). In order to investigate the functional effect of the patient-derived mutation, LDCV cargo secretion was stimulated and secretory output was determined. Cargo secretion is significantly reduced in disease-modeling cells, which is likely caused by impaired LDCV biogenesis since defective HID1 protein leads to diminished protein expression of the LDCV cargo protein and biogenesis driver secretogranin II (SGII), probably due to downregulation of SCG2 gene expression. Furthermore, highly diminished cytosolic signal of LDCV marker protein chromogranin A indicates accumulation of LDCV cargo at the trans-Golgi network in the absence of HID1 protein, which may be caused by defective vesicle formation. Along with the significantly reduced secretion of LDCV cargo, known to have neuromodulating functions, disease-modeling cells exhibit aberrant ability to differentiate into mature neurons. Cells show morphological differences as significantly reduced neurite outgrowth and clustering of cell soma. Also, pronounced cell death and diverging expression of differentiation markers and LDCV cargo proteins was observed. In conclusion, this study could show that HID1 is involved in LDCV biogenesis by affecting cargo protein biosynthesis and vesicle formation. Furthermore, the data point towards the involvement of HID1 in LDCV trafficking and neurodevelopment. Experiments with the patient-derived HID1 mutation indicate that the mutation is a loss-of-function mutation that negatively influences the secretion of hormones and neuromodulators. These defects are especially reflected in pituitary insufficiency and severe statomotor development delay in patients, substantiating the assumption that detected HID1 mutation is pathogenic and thus is the driver of the neurological disease in the described patients.2023-08-2

Abiotic and biotic factors influencing the early development of kelps under global change scenarios

The cold-temperate kelp species Alaria esculenta, Saccharina latissima and Laminaria digitata co-occur at the same depth at a variety of locations. Due to their heteromorphic life cycle a large part of their development is only microscopically visible. We investigated the impact of sedimentation, temperature and light (as abiotic factors) and interspecific competition and grazing (as biotic factors) on early developmental stages in multi-factorial approaches. The germination success, speed of gametogenesis and survival of juvenile sporophytes were followed in laboratory and field experiments. Although germination is mostly an autonomous process it was negatively affected by unfavourable abiotic conditions, especially high sediment load. Speed of gametogenesis was temperature dependent with species-specific optima. The recruitment success of young sporophytes was dependent on all interacting abiotic factors which also influenced the resource competition between the different species. For example, juvenile A. esculenta sporophytes overgrew L. digitata at 5 °C, while they had no competitive chance at 15 °C. High sediment loads were most detrimental for sporophyte survival, but interestingly, moderate grazing could decrease the negative impact of intermediate sediment loads. It became evident that many factors influence the outcome of recruitment in kelps and that changing temperature or increased sedimentation lead to a species-specific reaction which may influence the outcome of competition and thereby community structure. More field experiments are required to get ecologically relevant data because survival rates in the field were much lower compared to controlled laboratory conditions despite density control of spores in comparative experiments

Disrupted hippocampal sharp-wave ripple-associated spike dynamics in a transgenic mouse model of dementia

KEY POINTS: High frequency (100–250 Hz) neuronal oscillations in the hippocampus, known as sharp‐wave ripples (SWRs), synchronise the firing behaviour of groups of neurons and play a key role in memory consolidation. Learning and memory are severely compromised in dementias such as Alzheimer's disease; however, the effects of dementia‐related pathology on SWRs are unknown. The frequency and temporal structure of SWRs was disrupted in a transgenic mouse model of tauopathy (one of the major hallmarks of several dementias). Excitatory pyramidal neurons were more likely to fire action potentials in a phase‐locked manner during SWRs in the mouse model of tauopathy; conversely, inhibitory interneurons were less likely to fire phase‐locked spikes during SWRs. These findings indicate there is reduced inhibitory control of hippocampal network events and point to a novel mechanism which may underlie the cognitive impairments in this model of dementia. ABSTRACT: Neurons within the CA1 region of the hippocampus are co‐activated during high frequency (100–250 Hz) sharp‐wave ripple (SWR) activity in a manner that probably drives synaptic plasticity and promotes memory consolidation. In this study we have used a transgenic mouse model of dementia (rTg4510 mice), which overexpresses a mutant form of tau protein, to examine the effects of tauopathy on hippocampal SWRs and associated neuronal firing. Tetrodes were used to record simultaneous extracellular action potentials and local field potentials from the dorsal CA1 pyramidal cell layer of 7‐ to 8‐month‐old wild‐type and rTg4510 mice at rest in their home cage. At this age point these mice exhibit neurofibrillary tangles, neurodegeneration and cognitive deficits. Epochs of sleep or quiet restfulness were characterised by minimal locomotor activity and a low theta/delta ratio in the local field potential power spectrum. SWRs detected off‐line were significantly lower in amplitude and had an altered temporal structure in rTg4510 mice. Nevertheless, the average frequency profile and duration of the SWRs were relatively unaltered. Putative interneurons displayed significantly less temporal and phase locking to SWRs in rTg4510 mice, whilst putative pyramidal neurons showed increased temporal and phase locking to SWRs. These findings indicate there is reduced inhibitory control of hippocampal network events and point to a novel mechanism which may contribute to impairments in memory consolidation in this model of dementia

The polysemous concepts of psychomotricity and catatonia: A European multi-consensus perspective.

Current classification systems use the terms "catatonia" and "psychomotor phenomena" as mere a-theoretical descriptors, forgetting about their theoretical embedment. This was the source of misunderstandings among clinicians and researchers of the European collaboration on movement and sensorimotor/psychomotor functioning in schizophrenia and other psychoses or ECSP. Here, we review the different perspectives, their historical roots and highlight discrepancies. In 1844, Wilhelm Griesinger coined the term "psychic-motor" to name the physiological process accounting for volition. While deriving from this idea, the term "psychomotor" actually refers to systems that receive miscellaneous intrapsychic inputs, convert them into coherent behavioral outputs send to the motor systems. More recently, the sensorimotor approach has drawn on neuroscience to redefine the motor signs and symptoms observed in psychoses. In 1874, Karl Kahlbaum conceived catatonia as a brain disease emphasizing its somatic - particularly motor - features. In conceptualizing dementia praecox Emil Kraepelin rephrased catatonic phenomena in purely mental terms, putting aside motor signs which could not be explained in this way. Conversely, the Wernicke-Kleist-Leonhard school pursued Kahlbaum's neuropsychiatric approach and described many new psychomotor signs, e.g. parakinesias, Gegenhalten. They distinguished 8 psychomotor phenotypes of which only 7 are catatonias. These barely overlap with consensus classifications, raising the risk of misunderstanding. Although coming from different traditions, the authors agreed that their differences could be a source of mutual enrichment, but that an important effort of conceptual clarification remained to be made. This narrative review is a first step in this direction

Author Correction: SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

An amendment to this paper has been published and can be accessed via a link at the top of the paper

SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Versiones preprint disponibles en: http://hdl.handle.net/10261/216920 y http://hdl.handle.net/10261/217161Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here, we demonstrate that the NRF2 antioxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular antiviral program that potently inhibits replication of SARS-CoV2 across cell lines. The inhibitory effect of 4-OI and DMF extends to the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, 4-OI and DMF limit host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and in suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2.This research work was supported by Ester M og Konrad Kristian Sigurdssons Dyreværnsfond, Beckett-Fonden, Kong Christian IX og Dronning Louises Jubilæumslegat, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis´ legat, Købmand I Odense Johan og Hanne Weimann Født Seedorffs Legat, Hørslev Fonden, UK Medical Research Council (MRC core funding of the MRC Human Immunology Unit; JR), Lundbeck foundation (R303-2018-3379 and R219-2016-878, and R268-2016-3927), and Independent Research Fund Denmark – Medical Sciences (9039-00078B, 4004-00047B, and 0214-00001B). CarlsbergFoundation (Semper Ardens) and European Research Council (ERC-AdG ENVISION; 786602). Marie Skłodowska-Curie Action of the European Commission # 813343 and Italian Cancer Research Society #22891 to JH.Peer reviewe

Consumer behavior : perilaku konsumen dan strategi pemasaran jilid 2

+hlm.;c