RT Journal Article
SR Electronic
T1 Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.19.427286
DO 10.1101/2021.01.19.427286
A1 Manik Kuchroo
A1 Marcello DiStasio
A1 Eda Calapkulu
A1 Maryam Ige
A1 Le Zhang
A1 Amar H. Sheth
A1 Madhvi Menon
A1 Yu Xing
A1 Scott Gigante
A1 Jessie Huang
A1 Rahul M. Dhodapkar
A1 Bastian Rieck
A1 Guy Wolf
A1 Smita Krishnaswamy
A1 Brian P. Hafler
YR 2021
UL http://biorxiv.org/content/early/2021/01/20/2021.01.19.427286.abstract
AB A novel topological machine learning approach applied to single-nucleus RNA sequencing from human retinas with age-related macular degeneration identifies interacting disease phase-specific glial activation states shared with Alzheimer’s disease and multiple sclerosis.Abstract Neurodegeneration occurs in a wide range of diseases, including age-related macular degeneration (AMD), Alzheimer’s disease (AD), and multiple sclerosis (MS), each with distinct inciting events. To determine whether glial transcriptional states are shared across phases of degeneration, we sequenced 50,498 nuclei from the retinas of seven AMD patients and six healthy controls, generating the first single-cell transcriptomic atlas of AMD. We identified groupings of cells implicated in disease pathogenesis by applying a novel topologically-inspired machine learning approach called ‘diffusion condensation.’ By calculating diffusion homology features and performing persistence analysis, diffusion condensation identified activated glial states enriched in the early phases of AMD, AD, and MS as well as an AMD-specific proangiogenic astrocyte state promoting pathogenic neovascularization in advanced AMD. Finally, by mapping the expression of disease-associated genes to glial states, we identified key signaling interactions creating hypotheses for therapeutic intervention. Our topological analysis identified an integrated disease-phase specific glial landscape that is shared across neurodegenerative conditions affecting the central nervous system.Competing Interest StatementThe authors have declared no competing interest.