Spatiotemporal Insights Into RNA-Organelle Interactions in Neurons.
Ontology highlight
ABSTRACT:
SUBMITTER: Kharod SC
PROVIDER: S-EPMC8222803 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Retrograde transport from endosomes to the trans-Golgi network (TGN) diverts proteins and lipids away from lysosomal degradation. It is essential for maintaining cellular homeostasis and signaling. In recent years, significant advancements have been made in understanding this classical pathway, revealing new insights into multiple steps of vesicular trafficking as well as critical roles of ER-endosome contacts for endosomal trafficking. In this review, we summarize up-to-date knowledge about this trafficking pathway, in particular, mechanisms of cargo recognition at endosomes and vesicle tethering at the TGN, and contributions of ER-endosome contacts.
| S-EPMC7093645 | biostudies-literature
Project description:Following mitosis, daughter cells must inherit a functional set of essential proteins and organelles. We applied a genetic tool to simultaneously monitor the kinetics and distribution of old and new proteins marking all intracellular compartments in budding yeasts. Most organelles followed a general pattern whereby preexisting proteins are symmetrically partitioned followed by template-based incorporation of new proteins. Peroxisomes belong to this group, supporting a model of biogenesis by growth and division from preexisting peroxisomes. We detected two exceptions: the nuclear pore complex (NPC) and the spindle pole body (SPB). Old NPCs are stably inherited during successive generations but remained separated from new NPCs, which are incorporated de novo in mother and daughter cells. Only the SPB displayed asymmetrical distribution, with old components primarily inherited by daughter cells and new proteins equally incorporated in both cells. Our analysis resolves conflicting models (peroxisomes, NPC) and reveals unique patterns (NPC, SPB) of organelle inheritance.
| S-EPMC3538235 | biostudies-literature
Project description:RNA-binding proteins (RBPs) have been shown to play a key role in the pathogenesis of a variety of neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is an exemplar neurodegenerative disease characterised by rapid progression and relatively selective motor neuron loss. Nuclear-to-cytoplasmic mislocalisation and accumulation of RBPs have been identified as a pathological hallmark of the disease, yet the spatiotemporal responses of RBPs to different extrinsic stressors in human neurons remain incompletely understood. Here, we used healthy induced pluripotent stem cell (iPSC)-derived motor neurons to model how different types of cellular stress affect the nucleocytoplasmic localisation of key ALS-linked RBPs. We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manner. Interestingly, we found that RBPs displayed stress-dependent characteristics, with unique responses to both heat and oxidative stress. Alongside nucleocytoplasmic protein distribution changes, we identified the formation of stress- and RBP-specific nuclear and cytoplasmic foci. Furthermore, the kinetics of nuclear relocalisation upon recovery from extrinsic stressors was also found to be both stress- and RBP-specific. Importantly, these experiments specifically highlight TDP-43 and FUS, two of the most recognised RBPs in ALS pathogenesis, as exhibiting delayed nuclear relocalisation following stress in healthy human motor neurons as compared to SFPQ, hnRNPA1 and hnRNPK. Notably, ALS-causing valosin containing protein (VCP) mutations did not disrupt the relocalisation dynamics of TDP-43 or FUS in human motor neurons following stress. An increased duration of TDP-43 and FUS within the cytoplasm after stress may render the environment more aggregation-prone, which may be poorly tolerated in the context of ALS and related neurodegenerative disorders. In summary, our study addresses stress-specific spatiotemporal responses of neurodegeneration-related RBPs in human motor neurons. The insights into the nucleocytoplasmic dynamics of RBPs provided here may be informative for future studies examining both disease mechanisms and therapeutic strategy.
| S-EPMC7664327 | biostudies-literature
Project description:Design of reversible organelle-like microcompartments formed by liquid-liquid phase separation in cell-mimicking entities has significantly advanced the bottom-up construction of artificial eukaryotic cells. However, organizing the formation of artificial organelle architectures in a spatiotemporal manner within complex primitive compartments remains scarcely explored. In this work, thermoresponsive hybrid polypeptide-polymer conjugates are rationally engineered and synthesized, resulting from the conjugation of an intrinsically disordered synthetic protein (IDP), namely elastin-like polypeptide, and synthetic polymers (poly(ethylene glycol) and dextran) that are widely used as macromolecular crowding agents. Cell-like constructs are built using droplet-based microfluidics that are filled with such bioconjugates and an artificial cytoplasm system that is composed of specific polymers conjugated to the IDP. The distinct spatial organizations of two polypeptide-polymer conjugates and the dynamic assembly and disassembly of polypeptide-polymer coacervate droplets in response to temperature are studied in the cytomimetic protocells. Furthermore, a monoblock IDP with longer length is concurrently included with bioconjugates individually inside cytomimetic compartments. Both bioconjugates exhibit an identical surfactant-like property, compartmentalizing the monoblock IDP coacervates via temperature control. These findings lay the foundation for developing hierarchically structured synthetic cells with interior organelle-like structures which could be designed to localize in desired phase-separated subcompartments.
| S-EPMC8693077 | biostudies-literature
Project description:Membrane-bound organelles in eukaryotic cells form an interactive network to coordinate and facilitate cellular functions. The formation of close contacts, termed "membrane contact sites" (MCSs), represents an intriguing strategy for organelle interaction and coordinated interplay. Emerging research is rapidly revealing new details of MCSs. They represent ubiquitous and diverse structures, which are important for many aspects of cell physiology and homeostasis. Here, we provide a comprehensive overview of the physiological relevance of organelle contacts. We focus on mitochondria, peroxisomes, the Golgi complex and the plasma membrane, and discuss the most recent findings on their interactions with other subcellular organelles and their multiple functions, including membrane contacts with the ER, lipid droplets and the endosomal/lysosomal compartment.
| S-EPMC7377706 | biostudies-literature
Project description:It is generally accepted that visual perception results from the activation of a feed-forward hierarchy of areas, leading to increasingly complex representations. Here we present evidence for a fundamental role of backward projections to the occipito-temporal region for understanding conceptual object properties. The evidence is based on two studies. In the first study, using high-density EEG, we showed that during the observation of how objects are used there is an early activation of occipital and temporal areas, subsequently reaching the pole of the temporal lobe, and a late reactivation of the visual areas. In the second study, using transcranial magnetic stimulation over the occipital lobe, we showed a clear impairment in the accuracy of recognition of how objects are used during both early activation and, most importantly, late occipital reactivation. These findings represent strong neurophysiological evidence that a top-down mechanism is fundamental for understanding conceptual object properties, and suggest that a similar mechanism might be also present for other higher-order cognitive functions.
| S-EPMC3791766 | biostudies-other
Project description:PurposeVision loss due to retinitis pigmentosa affects an estimated 15 million people worldwide. Through collaboration between Second Sight Medical Products, Inc., and the Doheny Eye Institute, six blind human subjects underwent implantation with epiretinal 4 x 4 electrode arrays designed to directly stimulate the remaining cells of the retina, with the goal of restoring functional vision by applying spatiotemporal patterns of stimulation. To better understand spatiotemporal interactions between electrodes during synchronous and asynchronous stimulation, the authors investigated how percepts changed as a function of pulse timing across the electrodes.MethodsPulse trains (20, 40, 80, and 160 Hz) were presented on groups of electrodes with 800, 1600, or 2400 microm center-to-center separation. Stimulation was either synchronous (pulses were presented simultaneously across electrodes) or asynchronous (pulses were phase shifted). Using a same-different discrimination task, the authors were able to evaluate how the perceptual quality of the stimuli changed as a function of phase shifts across multiple electrodes.ResultsEven after controlling for electric field interactions, subjects could discriminate between spatiotemporal pulse train patterns based on differences of phase across electrodes as small as 3 ms. These findings suggest that the quality of the percept is affected not only by electric field interactions but also by spatiotemporal interactions at the neural level.ConclusionsDuring multielectrode stimulation, interactions between electrodes have a significant influence on the quality of the percept. Understanding how these spatiotemporal interactions at the neural level influence percepts during multielectrode stimulation is fundamental to the successful design of a retinal prosthesis.
| S-EPMC2868442 | biostudies-literature
Project description:Spatial integration of transcription and splicing in a dedicated compartment sustains monogenic antigen expression in African trypanosomes
| PRJEB35632 | ENA
Project description:Working memory is capacity-limited. In everyday life we rarely notice this limitation, in part because we develop behavioral strategies that help mitigate the capacity limitation. How behavioral strategies are mediated at the neural level is unclear, but a likely locus is lateral prefrontal cortex (LPFC). Neurons in LPFC play a prominent role in working memory and have been shown to encode behavioral strategies. To examine the role of LPFC in overcoming working-memory limitations, we recorded the activity of LPFC neurons in animals trained to perform a serial self-ordered search task. This task measured the ability to prospectively plan the selection of unchosen spatial search targets while retrospectively tracking which targets were previously visited. We found that individual LPFC neurons encoded the spatial location of the current search target but also encoded the spatial location of targets up to several steps away in the search sequence. Neurons were more likely to encode prospective than retrospective targets. When subjects used a behavioral strategy of stereotyped target selection, mitigating the working-memory requirements of the task, not only did the number of selection errors decrease but there was a significant reduction in the strength of spatial encoding in LFPC. These results show that LPFC neurons have spatiotemporal mnemonic fields, in that their firing rates are modulated both by the spatial location of future selection behaviors and the temporal organization of that behavior. Furthermore, the strength of this tuning can be dynamically modulated by the demands of the task.
| S-EPMC5949014 | biostudies-literature
Project description:Alzheimer's disease (AD) is the most common cause of dementia, with no current cure. Consequently, alternative approaches focusing on early pathological events in specific neuronal populations, besides targeting the well-studied amyloid beta (Aβ) accumulations and Tau tangles, are needed. In this study, we have investigated disease phenotypes specific to glutamatergic forebrain neurons and mapped the timeline of their occurrence, by implementing familial and sporadic human induced pluripotent stem cell models as well as the 5xFAD mouse model. We recapitulated characteristic late AD phenotypes, such as increased Aβ secretion and Tau hyperphosphorylation, as well as previously well documented mitochondrial and synaptic deficits. Intriguingly, we identified Golgi fragmentation as one of the earliest AD phenotypes, indicating potential impairments in protein processing and post-translational modifications. Computational analysis of RNA sequencing data revealed differentially expressed genes involved in glycosylation and glycan patterns, whilst total glycan profiling revealed minor glycosylation differences. This indicates general robustness of glycosylation besides the observed fragmented morphology. Importantly, we identified that genetic variants in Sortilin-related receptor 1 (SORL1) associated with AD could aggravate the Golgi fragmentation and subsequent glycosylation changes. In summary, we identified Golgi fragmentation as one of the earliest disease phenotypes in AD neurons in various in vivo and in vitro complementary disease models, which can be exacerbated via additional risk variants in SORL1.
| S-EPMC9978754 | biostudies-literature