Altered perivascular fibroblast activity precedes ALS disease onset

Anna Månberg, Nathan Skene, Folkert Sanders, Marta Trusohamn, Julia Remnestål, Anna Szczepińska, Inci Sevval Aksoylu, Peter Lönnerberg, Lwaki Ebarasi, Stefan Wouters, Manuela Lehmann, Jennie Olofsson, Inti von Gohren Antequera, Aylin Domaniku, Maxim de Schaepdryver, Joke de Vocht, Koen Poesen, Mathias Uhlén, Jasper Anink, Caroline MijnsbergenHermieneke Vergunst-Bosch, Annemarie Hübers, Ulf Kläppe, Elena Rodriguez-Vieitez, Jonathan D. Gilthorpe, Eva Hedlund, Robert A. Harris, Eleonora Aronica, Philip van Damme, Albert Ludolph, Jan Veldink, Caroline Ingre, Peter Nilsson, Sebastian A. Lewandowski

Research output: Contribution to JournalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)640-646
Number of pages7
JournalNature Medicine
Issue number4
Publication statusPublished - 1 Apr 2021

Cite this