Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis

Maniatis, Silas; Äijö, Tarmo; Vicković, Sanja; Braine, Catherine E.; Kang, Kristy; Mollbrink, Annelie; Fagegaltier, Delphine; Andrusivová, Žaneta; Saarenpää, Sami; Saiz-Castro, Gonzalo; Cuevas, Miguel; Watters, Aaron; Lundeberg, Joakim; Bonneau, Richard; Phatnani, Hemali

doi:10.1126/science.aav9776

Cited by 362 publications

(342 citation statements)

References 39 publications

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“…The Visium platform expands the spatial resolution 5-fold beyond the first-generation 'Spatial Transcriptomics' approach (Ståhl et al, 2016) upon which it is based. While the original approach was successfully used to generate gene expression atlases and identify perturbations in transcriptional pathways for several normal and pathological human tissues, including the developing heart (Asp et al, 2018) , invasive ductal cancer (Ståhl et al, 2016) , pancreatic ductal adenocarcinoma (Moncada et al, 2018) , prostate cancer (Berglund et al, 2018) , postmortem spinal cord (Maniatis et al, 2019) and cerebellum (Gregory et al, 2020) of patients with amyotrophic lateral sclerosis (ALS), it lacked the necessary spatial resolution to resolve both individual cells and laminar structures in the human cortex.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

Maynard

Collado‐Torres

Weber³

et al. 2020

Preprint

142

326

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We used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex (DLPFC). We identified extensive layer-enriched expression signatures, and refined associations to previous laminar markers. We overlaid our laminar expression signatures onto large-scale single nuclei RNA sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially-defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions where morphological architecture is not as well-defined as cortical laminae. We lastly created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research ( http://research.libd.org/spatialLIBD ).

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Section: Introductionmentioning

confidence: 99%

Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

Maynard

Collado‐Torres

Weber³

et al. 2020

Preprint

142

326

View full text Add to dashboard Cite

show abstract

“…While the Aβ plaque niche has been investigated using laser capture microdissection (Rothman et al, 2018;Xiong, Ge and Ma, 2019), these experiments involved pooling of the micro-dissected samples and information on original spatial localization, amyloid density, and cellular composition of the samples was lost. In contrast, the use of spatially barcoded arrays allows global unbiased transcriptome profiling maintaining the morphology of the tissue and the spatial localization of the sequenced molecules (Ståhl et al, 2016;Rodriques et al, 2019, Maniatis et al, 2019.…”

Section: Introductionmentioning

confidence: 99%

Spatial and temporal transcriptomics reveal microglia-astroglia crosstalk in the amyloid-β plaque cell niche of Alzheimer’s disease

Chen

Craessaerts

et al. 2019

Preprint

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The linear cause-consequence relationship linking amyloid-β peptide (Aβ) accumulation to neuronal dysfunction in Alzheimer disease (AD) is gradually replaced by the concept that Aβ initiates complex inflammatory-like cellular alterations that progressively become Aβ independent and lead to brain dyshomeostasis. Little is known about the pathophysiology of this cellular phase of AD. We use here two orthogonal technologies, Spatial Transcriptomics and in situ sequencing, to analyse the transcriptome changes in cells in the amyloid-β plaque niche in a knock-in mouse model for AD. We identify a multicellular co-expressed gene network of 57 Plaque-Induced Genes (PIGs) that define a series of co-ordinated and spatially restricted microglia, astroglia and oligodendrocyte responses to progressing amyloid plaques encompassing complement, oxidative stress and inflammation. A separate oligodendrocyte network suggests abnormal myelination. Spatial Transcriptomics provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.

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“…Despite their critical functional role, spinal motor neurons make up less than 0.4% of the total cells in the mammalian spinal cord 9 . This rarity has made them notoriously difficult to transcriptionally characterize 10 . To overcome these hurdles, we developed a motor neuron enrichment strategy using a fluorescent reporter mouse.…”

Section: Mainmentioning

confidence: 99%

Single-cell transcriptomic analysis of the adult mouse spinal cord

Blum

Klemm

Nakayama

et al. 2020

Preprint

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The spinal cord is a fascinating structure responsible for coordinating all movement in vertebrates. Spinal motor neurons control the activity of virtually every organ and muscle throughout the body by transmitting signals that originate in the spinal cord. These neurons are remarkably heterogeneous in their activity and innervation targets. However, because motor neurons represent only a small fraction of cells within the spinal cord and are difficult to isolate, the full complement of motor neuron subtypes remains unknown. Here we comprehensively describe the molecular heterogeneity of motor neurons within the adult spinal cord. We profiled 43,890 single-nucleus transcriptomes using fluorescence-activated nuclei sorting to enrich for spinal motor neuron nuclei. These data reveal a transcriptional map of the adult mammalian spinal cord and the first unbiased characterization of all transcriptionally distinct autonomic and somatic spinal motor neuron subpopulations. We identify 16 sympathetic motor neuron subtypes that segregate spatially along the spinal cord. Many of these subtypes selectively express specific hormones and receptors, suggesting neuromodulatory signaling within the autonomic nervous system. We describe skeletal motor neuron heterogeneity in the adult spinal cord, revealing numerous novel markers that distinguish alpha and gamma motor neurons—cell populations that are specifically affected in neurodegenerative disease. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neurons. Collectively, these data provide a single-cell transcriptional atlas for investigating motor neuron diversity as well as the cellular and molecular basis of motor neuron function in health and disease.

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Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis

Cited by 362 publications

References 39 publications

Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

Transcriptome-scale spatial gene expression in the human dorsolateral prefrontal cortex

Spatial and temporal transcriptomics reveal microglia-astroglia crosstalk in the amyloid-β plaque cell niche of Alzheimer’s disease

Single-cell transcriptomic analysis of the adult mouse spinal cord

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