scholarly journals Simultaneous pathway engagement of translation in astrocytes, circadian rhythm in GABAergic neurons and cytoskeleton in glutamatergic neurons precede electroencephalographic changes in neurodegenerative prion disease

2021 ◽  
Author(s):  
Lech Tadeusz Kaczmarczyk ◽  
Melvin Schleif ◽  
Lars Dittrich ◽  
Rhiannan Williams ◽  
Marusa Koderman ◽  
...  
Keyword(s):  
Circadian Rhythm ◽  
Prion Disease ◽  
Disease Onset ◽  
Disease Process ◽  
Cell Types ◽  
Brain Regions ◽  
Inhibitory Neurons ◽  
Clinical Feature ◽  
Outward Appearance ◽  
Theta Power

Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific brain regions and cell types. This selectivity may arise from cells possessing varying capacities to regain proteostasis when stressed by cytotoxic protein conformers. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite having a normal outward appearance. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated a sharply reduced synthesis of ribosomal and mitochondrial components, 2) excitatory neurons showed increased expression of cytoskeletal genes, and 3) inhibitory neurons revealed reduced expression of circadian rhythm network genes. Further assessment for the role of circadian rhythms using a jet lag paradigm modestly exacerbated disease. These data demonstrate that early translatome responses to neurodegeneration emerge prior to other signs of disease and are unique to different cell types. Therapeutic strategies may need to target multiple pathways, each in specific populations of cells, early in the disease process.

scholarly journals Prevalent presence of periodic actin–spectrin-based membrane skeleton in a broad range of neuronal cell types and animal species

2016 ◽  
Vol 113 (21) ◽  
pp. 6029-6034 ◽  
Author(s):  
Jiang He ◽  
Ruobo Zhou ◽  
Zhuhao Wu ◽  
Monica A. Carrasco ◽  
Peri T. Kurshan ◽  
...  
Keyword(s):  
Glial Cell ◽  
Animal Species ◽  
Homo Sapiens ◽  
Neuronal Cell ◽  
Cell Types ◽  
Membrane Skeleton ◽  
Brain Regions ◽  
Inhibitory Neurons ◽  
Periodic Distribution ◽  
Neuronal Types

Actin, spectrin, and associated molecules form a periodic, submembrane cytoskeleton in the axons of neurons. For a better understanding of this membrane-associated periodic skeleton (MPS), it is important to address how prevalent this structure is in different neuronal types, different subcellular compartments, and across different animal species. Here, we investigated the organization of spectrin in a variety of neuronal- and glial-cell types. We observed the presence of MPS in all of the tested neuronal types cultured from mouse central and peripheral nervous systems, including excitatory and inhibitory neurons from several brain regions, as well as sensory and motor neurons. Quantitative analyses show that MPS is preferentially formed in axons in all neuronal types tested here: Spectrin shows a long-range, periodic distribution throughout all axons but appears periodic only in a small fraction of dendrites, typically in the form of isolated patches in subregions of these dendrites. As in dendrites, we also observed patches of periodic spectrin structures in a small fraction of glial-cell processes in four types of glial cells cultured from rodent tissues. Interestingly, despite its strong presence in the axonal shaft, MPS is disrupted in most presynaptic boutons but is present in an appreciable fraction of dendritic spine necks, including some projecting from dendrites where such a periodic structure is not observed in the shaft. Finally, we found that spectrin is capable of adopting a similar periodic organization in neurons of a variety of animal species, including Caenorhabditis elegans, Drosophila, Gallus gallus, Mus musculus, and Homo sapiens.

scholarly journals Single-nuclei transcriptomics of schizophrenia prefrontal cortex primarily implicates neuronal subtypes

2020 ◽  
Author(s):  
Benjamin C. Reiner ◽  
Richard C. Crist ◽  
Lauren M. Stein ◽  
Andrew E. Weller ◽  
Glenn A. Doyle ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Differentially Expressed Genes ◽  
Neuronal Cell ◽  
Cell Types ◽  
Brain Regions ◽  
Differentially Expressed ◽  
Inhibitory Neurons ◽  
Specific Cell ◽  
Dorsolateral Prefrontal ◽  
Layer V

AbstractTranscriptomic studies of bulk neural tissue homogenates from persons with schizophrenia and controls have identified differentially expressed genes in multiple brain regions. However, the heterogeneous nature prevents identification of relevant cell types. This study analyzed single-nuclei transcriptomics of ∼311,000 nuclei from frozen human postmortem dorsolateral prefrontal cortex samples from individuals with schizophrenia (n = 14) and controls (n = 16). 2,846 differential expression events were identified in 2,195 unique genes in 19 of 24 transcriptomically-distinct cell populations. ∼97% of differentially expressed genes occurred in five neuronal cell types, with ∼63% occurring in a subtype of PVALB+ inhibitory neurons and HTR2C+ layer V excitatory neurons. Differentially expressed genes were enriched for genes localized to schizophrenia GWAS loci. Cluster-specific changes in canonical pathways, upstream regulators and causal networks were identified. These results expand our knowledge of disrupted gene expression in specific cell types and permit new insight into the pathophysiology of schizophrenia.

scholarly journals Extracellular Interactions of Alpha-Synuclein in Multiple System Atrophy

2018 ◽  
Vol 19 (12) ◽  
pp. 4129 ◽  
Author(s):  
Dario Valdinocci ◽  
Rowan Radford ◽  
Michael Goulding ◽  
Junna Hayashi ◽  
Roger Chung ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Disease Process ◽  
Neuronal Cell ◽  
Cell Loss ◽  
Cell Types ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Current Evidence ◽  
Extracellular Milieu ◽  
The Brain

Multiple system atrophy, characterized by atypical Parkinsonism, results from central nervous system (CNS) cell loss and dysfunction linked to aggregates of the normally pre-synaptic α-synuclein protein. Mostly cytoplasmic pathological α-synuclein inclusion bodies occur predominantly in oligodendrocytes in affected brain regions and there is evidence that α-synuclein released by neurons is taken up preferentially by oligodendrocytes. However, extracellular α-synuclein has also been shown to interact with other neural cell types, including astrocytes and microglia, as well as extracellular factors, mediating neuroinflammation, cell-to-cell spread and other aspects of pathogenesis. Here, we review the current evidence for how α-synuclein present in the extracellular milieu may act at the cell surface to drive components of disease progression. A more detailed understanding of the important extracellular interactions of α-synuclein with neuronal and non-neuronal cell types both in the brain and periphery may provide new therapeutic targets to modulate the disease process.

scholarly journals Novel Morphological Glial Alterations in the Spectrum of Prion Disease Types: A Focus on Common Findings

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 596
Author(s):  
Moisés Garcés ◽  
Isabel M. Guijarro ◽  
Diane L. Ritchie ◽  
Juan J. Badiola ◽  
Marta Monzón
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Prion Diseases ◽  
Immunological Response ◽  
Cell Types ◽  
Ultrastructural Level ◽  
Brain Regions ◽  
Protein Accumulation ◽  
Pathological Changes ◽  
Neurodegenerative Process

Human prion diseases are a group of rare fatal neurodegenerative diseases with sporadic, genetic, and acquired forms. They are neuropathologically characterized by pathological prion protein accumulation, neuronal death, and vacuolation. Classical immunological response has long been known not to play a major in prion diseases; however, gliosis is known to be a common feature although variable in extent and poorly described. In this investigation, astrogliosis and activated microglia in two brain regions were assessed and compared with non-neurologically affected patients in a representative sample across the spectrum of Creutzfeldt–Jakob disease (CJD) forms and subtypes in order to analyze the influence of prion strain on pathological processes. In this report, we choose to focus on features common to all CJD types rather than the diversity among them. Novel pathological changes in both glial cell types were found to be shared by all CJD types. Microglial activation correlated to astrogliosis. Spongiosis, but not pathological prion protein deposition, correlated to both astrogliosis and microgliosis. At the ultrastructural level, astrocytic glial filaments correlated with pathological changes associated with prion disease. These observations confirm that neuroglia play a prominent role in the neurodegenerative process of prion diseases, regardless of the causative prion type.

scholarly journals GABAergic Neuron Specification in the Spinal Cord, the Cerebellum, and the Cochlear Nucleus

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Kei Hori ◽  
Mikio Hoshino
Keyword(s):  
Spinal Cord ◽  
Nervous System ◽  
Cochlear Nucleus ◽  
Neuronal Cell ◽  
Cell Types ◽  
Brain Regions ◽  
Lineage Tracing ◽  
Inhibitory Neurons ◽  
Genetic Lineage ◽  
Genetic Lineage Tracing

In the nervous system, there are a wide variety of neuronal cell types that have morphologically, physiologically, and histochemically different characteristics. These various types of neurons can be classified into two groups: excitatory and inhibitory neurons. The elaborate balance of the activities of the two types is very important to elicit higher brain function, because its imbalance may cause neurological disorders, such as epilepsy and hyperalgesia. In the central nervous system, inhibitory neurons are mainly represented by GABAergic ones with some exceptions such as glycinergic. Although the machinery to specify GABAergic neurons was first studied in the telencephalon, identification of key molecules, such as pancreatic transcription factor 1a (Ptf1a), as well as recently developed genetic lineage-tracing methods led to the better understanding of GABAergic specification in other brain regions, such as the spinal cord, the cerebellum, and the cochlear nucleus.

scholarly journals Cerebrospinal Fluid Biomarkers of Neurovascular Dysfunction in Mild Dementia and Alzheimer'S Disease

2015 ◽  
Vol 35 (7) ◽  
pp. 1055-1068 ◽  
Author(s):  
Melanie D Sweeney ◽  
Abhay P Sagare ◽  
Berislav V Zlokovic
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Neurovascular Unit ◽  
Disease Onset ◽  
Disease Process ◽  
Amyloid Β ◽  
Cell Types ◽  
Age Related ◽  
Cerebrospinal Fluid Biomarkers

Alzheimer's disease (AD) is the most common form of age-related dementias. In addition to genetics, environment, and lifestyle, growing evidence supports vascular contributions to dementias including dementia because of AD. Alzheimer's disease affects multiple cell types within the neurovascular unit (NVU), including brain vascular cells (endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes and microglia), and neurons. Thus, identifying and integrating biomarkers of the NVU cell-specific responses and injury with established AD biomarkers, amyloid-β (Aβ) and tau, has a potential to contribute to better understanding of the disease process in dementias including AD. Here, we discuss the existing literature on cerebrospinal fluid biomarkers of the NVU cell-specific responses during early stages of dementia and AD. We suggest that the clinical usefulness of established AD biomarkers, Aβ and tau, could be further improved by developing an algorithm that will incorporate biomarkers of the NVU cell-specific responses and injury. Such biomarker algorithm could aid in early detection and intervention as well as identify novel treatment targets to delay disease onset, slow progression, and/or prevent AD.

scholarly journals Prevalent Presence of Periodic Actin-spectrin-based Membrane Skeleton in a Broad Range of Neuronal Cell Types and Animal Species

2016 ◽  
Author(s):  
Jiang He ◽  
Ruobo Zhou ◽  
Zhuhao Wu ◽  
Monica Carrasco ◽  
Peri Kurshan ◽  
...  
Keyword(s):  
Glial Cell ◽  
Animal Species ◽  
Homo Sapiens ◽  
Neuronal Cell ◽  
Cell Types ◽  
Membrane Skeleton ◽  
Brain Regions ◽  
Inhibitory Neurons ◽  
Periodic Distribution ◽  
Neuronal Types

AbstractActin, spectrin and associated molecules form a periodic, sub-membrane cytoskeleton in the axons of neurons. For a better understanding of this membrane-associated periodic skeleton (MPS), it is important to address how prevalent this structure is in different neuronal types, different subcellular compartments, and across different animal species. Here, we investigated the organization of spectrin in a variety of neuronal and glial-cell types. We observed the presence of MPS in all of the tested neuronal types cultured from mouse central and peripheral nervous systems, including excitatory and inhibitory neurons from several brain regions, as well as sensory and motor neurons. Quantitative analyses show that MPS is preferentially formed in axons in all neuronal types tested here: spectrin shows a long-range, periodic distribution throughout all axons, but only appears periodic in a small fraction of dendrites, typically in the form of isolated patches in sub-regions of these dendrites. As in dendrites, we also observed patches of periodic spectrin structures in a small fraction of glial-cell processes in four types of glial cells cultured from rodent tissues. Interestingly, despite its strong presence in the axonal shaft, MPS is absent in most presynaptic boutons, but is present in a substantial fraction of dendritic spine necks, including some projecting from dendrites where such a periodic structure is not observed in the shaft. Finally, we found that spectrin is capable of adopting a similar periodic organization in neurons of a variety of animal species, including Caenorhabditis elegans, Drosophila, Gallus gallus, Mus musculus and Homo sapiens.

scholarly journals Atlas of Inhibitory Neurons in the Mouse Brain

2021 ◽  
Author(s):  
Dimitri Rodarie ◽  
Csaba Veraszto ◽  
Yann Roussel ◽  
Michael Reimann ◽  
Daniel Keller ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Cell Types ◽  
Brain Regions ◽  
Inhibitory Interneuron ◽  
Brain Cell ◽  
Computational Method ◽  
Inhibitory Neurons ◽  
Rich Diversity ◽  
Wide Range

The mouse brain contains a rich diversity of inhibitory interneuron types that have been characterized by their patterns of gene expression. However, the distribution of these cell types across the mouse brain is still incomplete. We developed a computational method to establish a consensus on the estimate of the densities of different interneuron types across the mouse brain. This method allows the unbiased integration of diverse and disparate datasets into a framework to predict interneuron densities for uncharted brain regions. We constrained our estimates based on previously computed brain-wide neuron density data, gene expression from in situ hybridization image stacks together with a wide range of values reported in the literature. Using optimization, we derived coherent estimates of cell densities for the different interneuron types. We estimated that 20.3% of all neurons in the mouse brain are inhibitory. Among all inhibitory neurons, 18% predominantly express parvalbumin (PV), 16% express somatostatin (SST), 3% express vasoactive intestinal peptide (VIP), and the remainder 63% belong to the residual GABAergic population. Our pipeline is extensible, allowing new cell types or data to be integrated as they become available. The data, algorithms, software, and results of this pipeline are publicly available and update the Blue Brain Cell Atlas. We find that our density estimations improve as more literature values are integrated. This work therefore leverages the research community to collectively converge on the numbers of each cell type in each brain region.

Synaptic organization of the gustatory NST

1994 ◽  
Vol 52 ◽  
pp. 150-151
Author(s):  
M. C. Whitehead
Keyword(s):  
Central Nervous System ◽  
Dendritic Spines ◽  
Fundamental Problem ◽  
Cell Types ◽  
Brain Regions ◽  
Excitatory Synapses ◽  
Solitary Tract ◽  
Synaptic Organization ◽  
Synaptic Junctions ◽  
Afferent Terminals

A fundamental problem in taste research is to determine how gustatory signals are processed and disseminated in the mammalian central nervous system. An important first step toward understanding information processing is the identification of cell types in the nucleus of the solitary tract (NST) and their synaptic relationships with oral primary afferent terminals. Facial and glossopharyngeal (LIX) terminals in the hamster were labelled with HRP, examined with EM, and characterized as containing moderate concentrations of medium-sized round vesicles, and engaging in asymmetrical synaptic junctions. Ultrastructurally the endings resemble excitatory synapses in other brain regions.Labelled facial afferent endings in the RC subdivision synapse almost exclusively with distal dendrites and dendritic spines of NST cells. Most synaptic relationships between the facial synapses and the dendrites are simple. However, 40% of facial endings engage in complex synaptic relationships within glomeruli containing unlabelled axon endings particularly ones termed "SP" endings. SP endings are densely packed with small, pleomorphic vesicles and synapse with both the facial endings and their postsynaptic dendrites by means of nearly symmetrical junctions.

scholarly journals Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

2017 ◽  
Author(s):  
Hilary K. Finucane ◽  
Yakir A. Reshef ◽  
Verneri Anttila ◽  
Kamil Slowikowski ◽  
Alexander Gusev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Ex Vivo ◽  
Cell Types ◽  
Inhibitory Neurons ◽  
Biliary Cirrhosis ◽  
Expression Data ◽  
Specific Expression

ABSTRACTGenetics can provide a systematic approach to discovering the tissues and cell types relevant for a complex disease or trait. Identifying these tissues and cell types is critical for following up on non-coding allelic function, developing ex-vivo models, and identifying therapeutic targets. Here, we analyze gene expression data from several sources, including the GTEx and PsychENCODE consortia, together with genome-wide association study (GWAS) summary statistics for 48 diseases and traits with an average sample size of 169,331, to identify disease-relevant tissues and cell types. We develop and apply an approach that uses stratified LD score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We detect tissue-specific enrichments at FDR < 5% for 34 diseases and traits across a broad range of tissues that recapitulate known biology. In our analysis of traits with observed central nervous system enrichment, we detect an enrichment of neurons over other brain cell types for several brain-related traits, enrichment of inhibitory over excitatory neurons for bipolar disorder but excitatory over inhibitory neurons for schizophrenia and body mass index, and enrichments in the cortex for schizophrenia and in the striatum for migraine. In our analysis of traits with observed immunological enrichment, we identify enrichments of T cells for asthma and eczema, B cells for primary biliary cirrhosis, and myeloid cells for Alzheimer's disease, which we validated with independent chromatin data. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signal.

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