Altered perivascular fibroblast activity precedes ALS disease onset

Nat Med. 2021 Apr;27(4):640-646. doi: 10.1038/s41591-021-01295-9. Epub 2021 Apr 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / blood
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Biomarkers / metabolism
  • Blood Vessels / pathology*
  • Collagen Type VI / genetics
  • Collagen Type VI / metabolism
  • DNA-Binding Proteins / metabolism
  • Disease Progression
  • Fibroblasts / pathology*
  • Genetic Markers
  • Humans
  • Mice, Transgenic
  • Osteopontin / blood
  • Prognosis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Spinal Cord / pathology
  • Spinal Cord / ultrastructure
  • Superoxide Dismutase / genetics
  • Transcription, Genetic
  • Vascular Remodeling


  • Biomarkers
  • Col6a1 protein, human
  • Collagen Type VI
  • DNA-Binding Proteins
  • Genetic Markers
  • RNA, Messenger
  • SPP1 protein, human
  • Osteopontin
  • Superoxide Dismutase

Associated data

  • figshare/10.6084/m9.figshare.11632794
  • figshare/10.6084/m9.figshare.11635887
  • figshare/10.6084/m9.figshare.11628891
  • figshare/10.6084/m9.figshare.11628585
  • figshare/10.6084/m9.figshare.14035616