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Cross-disorder and disease-specific pathways in dementia revealed by single-cell genomics.
Rexach, Jessica E; Cheng, Yuyan; Chen, Lawrence; Polioudakis, Damon; Lin, Li-Chun; Mitri, Vivianne; Elkins, Andrew; Han, Xia; Yamakawa, Mai; Yin, Anna; Calini, Daniela; Kawaguchi, Riki; Ou, Jing; Huang, Jerry; Williams, Christopher; Robinson, John; Gaus, Stephanie E; Spina, Salvatore; Lee, Edward B; Grinberg, Lea T; Vinters, Harry; Trojanowski, John Q; Seeley, William W; Malhotra, Dheeraj; Geschwind, Daniel H.
  • Rexach JE; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address:
  • Cheng Y; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Chen L; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Polioudakis D; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Lin LC; Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
  • Mitri V; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Elkins A; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Han X; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Yamakawa M; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Yin A; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Calini D; Neuroscience and Rare Diseases, Roche Pharma Research and Early Development, F. Hoffman-LaRoche Ltd., Basel, Switzerland.
  • Kawaguchi R; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Ou J; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Huang J; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Williams C; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Robinson J; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Gaus SE; Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
  • Spina S; Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA.
  • Lee EB; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Grinberg LT; Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • Vinters H; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • Trojanowski JQ; Department of Pathology & Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • Seeley WW; Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA, USA.
  • Malhotra D; Neuroscience and Rare Diseases, Roche Pharma Research and Early Development, F. Hoffman-LaRoche Ltd., Basel, Switzerland.
  • Geschwind DH; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Institute of Precis
Cell ; 2024 Sep 09.
Article en En | MEDLINE | ID: mdl-39265576
ABSTRACT
The development of successful therapeutics for dementias requires an understanding of their shared and distinct molecular features in the human brain. We performed single-nuclear RNA-seq and ATAC-seq in Alzheimer's disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP), analyzing 41 participants and ∼1 million cells (RNA + ATAC) from three brain regions varying in vulnerability and pathological burden. We identify 32 shared, disease-associated cell types and 14 that are disease specific. Disease-specific cell states represent glial-immune mechanisms and selective neuronal vulnerability impacting layer 5 intratelencephalic neurons in AD, layer 2/3 intratelencephalic neurons in FTD, and layer 5/6 near-projection neurons in PSP. We identify disease-associated gene regulatory networks and cells impacted by causal genetic risk, which differ by disorder. These data illustrate the heterogeneous spectrum of glial and neuronal compositional and gene expression alterations in different dementias and identify therapeutic targets by revealing shared and disease-specific cell states.
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Texto completo: 1 Banco de datos: MEDLINE Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Año: 2024 Tipo del documento: Article