Single cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Trem2R47H Alzheimer’s risk gene mutation

Johnston, Kevin; Berackey, Bereket B; Tran, Kristine Minh; Gelber, Alon; Yu, Zhaoxia; MacGregor, Grant; Mukamel, Eran A; Tan, Zhiqun; Green, Kim; Xu, Xiangmin

doi:10.21203/rs.3.rs-3656139/v1

Cited by 3 publications

References 70 publications

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Single-cell spatial transcriptomics reveals molecular patterns of selective neuronal vulnerability to α-synuclein pathology in a transgenic mouse model of Lewy body disease

Horan-Portelance,

Iba,

Acri

et al. 2024

Preprint

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One of the unifying pathological hallmarks of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) is the presence of misfolded, aggregated, and often phosphorylated forms of the protein α-synuclein in neurons. α-Synuclein pathology appears in select populations of neurons throughout various cortical and subcortical regions, and little is currently known about why some neurons develop pathology while others are spared. Here, we utilized subcellular-resolution imaging-based spatial transcriptomics (IST) in a transgenic mouse model that overexpresses wild-type human α-synuclein (α-syn-tg) to evaluate patterns of selective neuronal vulnerability to α-synuclein pathology. By performing post-IST immunofluorescence for α-synuclein phosphorylated at Ser129 (pSyn), we identified cell types in the cortex and hippocampus that were vulnerable or resistant to developing pSyn pathology. Next, we investigated the transcriptional underpinnings of the observed selective vulnerability using a set of custom probes to detect genes involved in α-synuclein processing and toxicity. We identified expression of the kinase:substrate pairPlk2, which phosphorylates α-synuclein at Ser129, and humanSNCA(hSNCA), as underlying the selective vulnerability to pSyn pathology. Finally, we performed differential gene expression analysis, comparing non-transgenic cells to pSyn-and pSyn+α-syn-tg cells to reveal gene expression changes downstream ofhSNCAoverexpression and pSyn pathology, which included pSyn-dependent alterations in mitochondrial and endolysosomal genes. This study provides a comprehensive use case of IST, yielding new biological insights into the formation of α-synuclein pathology and its downstream effects in a PD/DLB mouse model.

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Single-cell spatial transcriptomics reveals molecular patterns of selective neuronal vulnerability to α-synuclein pathology in a transgenic mouse model of Lewy body disease

Horan-Portelance,

Iba,

Acri

et al. 2024

Preprint

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Multiplexed spatial transcriptomics methods and the application of expansion microscopy

Fortner,

Bucur

2024

Front. Cell Dev. Biol.

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While spatial transcriptomics has undeniably revolutionized our ability to study cellular organization, it has driven the development of a great number of innovative transcriptomics methods, which can be classified into in situ sequencing (ISS) methods, in situ hybridization (ISH) techniques, and next-generation sequencing (NGS)-based sequencing with region capture. These technologies not only refine our understanding of cellular processes, but also open up new possibilities for breakthroughs in various research domains. One challenge of spatial transcriptomics experiments is the limitation of RNA detection due to optical crowding of RNA in the cells. Expansion microscopy (ExM), characterized by the controlled enlargement of biological specimens, offers a means to achieve super-resolution imaging, overcoming the diffraction limit inherent in conventional microscopy and enabling precise visualization of RNA in spatial transcriptomics methods. In this review, we elaborate on ISS, ISH and NGS-based spatial transcriptomic protocols and on how performance of these techniques can be extended by the combination of these protocols with ExM. Moving beyond the techniques and procedures, we highlight the broader implications of transcriptomics in biology and medicine. These include valuable insight into the spatial organization of gene expression in cells within tissues, aid in the identification and the distinction of cell types and subpopulations and understanding of molecular mechanisms and intercellular changes driving disease development.

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Spatial Multi-Omics in Alzheimer’s Disease: A Multi-Dimensional Approach to Understanding Pathology and Progression

Ma,

Shi,

Dong

et al. 2024

CIMB

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Alzheimer’s Disease (AD) presents a complex neuropathological landscape characterized by hallmark amyloid plaques and neurofibrillary tangles, leading to progressive cognitive decline. Despite extensive research, the molecular intricacies contributing to AD pathogenesis are inadequately understood. While single-cell omics technology holds great promise for application in AD, particularly in deciphering the understanding of different cell types and analyzing rare cell types and transcriptomic expression changes, it is unable to provide spatial distribution information, which is crucial for understanding the pathological processes of AD. In contrast, spatial multi-omics research emerges as a promising and comprehensive approach to analyzing tissue cells, potentially better suited for addressing these issues in AD. This article focuses on the latest advancements in spatial multi-omics technology and compares various techniques. Additionally, we provide an overview of current spatial omics-based research results in AD. These technologies play a crucial role in facilitating new discoveries and advancing translational AD research in the future. Despite challenges such as balancing resolution, increasing throughput, and data analysis, the application of spatial multi-omics holds immense potential in revolutionizing our understanding of human disease processes and identifying new biomarkers and therapeutic targets, thereby potentially contributing to the advancement of AD research.

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Single cell spatial transcriptomics reveals distinct patterns of dysregulation in non-neuronal and neuronal cells induced by the Trem2R47H Alzheimer’s risk gene mutation

Cited by 3 publications

References 70 publications

Single-cell spatial transcriptomics reveals molecular patterns of selective neuronal vulnerability to α-synuclein pathology in a transgenic mouse model of Lewy body disease

Single-cell spatial transcriptomics reveals molecular patterns of selective neuronal vulnerability to α-synuclein pathology in a transgenic mouse model of Lewy body disease

Multiplexed spatial transcriptomics methods and the application of expansion microscopy

Spatial Multi-Omics in Alzheimer’s Disease: A Multi-Dimensional Approach to Understanding Pathology and Progression

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