Altered perivascular fibroblast activity precedes ALS disease onset
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
Apart from well-defined factors in neuronal cells1, only a few reports consider that the variability of sporadic amyotrophic lateral sclerosis (ALS) progression can depend on less-defined contributions from glia2,3 and blood vessels4. In this study we use an expression-weighted cell-type enrichment method to infer cell activity in spinal cord samples from patients with sporadic ALS and mouse models of this disease. Here we report that patients with sporadic ALS present cell activity patterns consistent with two mouse models in which enrichments of vascular cell genes preceded microglial response. Notably, during the presymptomatic stage, perivascular fibroblast cells showed the strongest gene enrichments, and their marker proteins SPP1 and COL6A1 accumulated in enlarged perivascular spaces in patients with sporadic ALS. Moreover, in plasma of 574 patients with ALS from four independent cohorts, increased levels of SPP1 at disease diagnosis repeatedly predicted shorter survival with stronger effect than the established risk factors of bulbar onset or neurofilament levels in cerebrospinal fluid. We propose that the activity of the recently discovered perivascular fibroblast can predict survival of patients with ALS and provide a new conceptual framework to re-evaluate definitions of ALS etiology.
Date Issued
2021-04-01
Date Acceptance
2021-02-24
Citation
Nature Medicine, 2021, 27 (4), pp.640-646
ISSN
1078-8956
Publisher
Nature Research
Start Page
640
End Page
646
Journal / Book Title
Nature Medicine
Volume
27
Issue
4
Copyright Statement
Copyright © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/33859435
PII: 10.1038/s41591-021-01295-9
Subjects
Amyotrophic Lateral Sclerosis
Animals
Biomarkers
Blood Vessels
Collagen Type VI
DNA-Binding Proteins
Disease Progression
Fibroblasts
Genetic Markers
Humans
Mice, Transgenic
Osteopontin
Prognosis
RNA, Messenger
Spinal Cord
Superoxide Dismutase
Transcription, Genetic
Vascular Remodeling
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2021-04-15