TY - JOUR
T1 - Altered perivascular fibroblast activity precedes ALS disease onset
AU - Månberg, Anna
AU - Skene, Nathan
AU - Sanders, Folkert
AU - Trusohamn, Marta
AU - Remnestål, Julia
AU - Szczepińska, Anna
AU - Aksoylu, Inci Sevval
AU - Lönnerberg, Peter
AU - Ebarasi, Lwaki
AU - Wouters, Stefan
AU - Lehmann, Manuela
AU - Olofsson, Jennie
AU - von Gohren Antequera, Inti
AU - Domaniku, Aylin
AU - de Schaepdryver, Maxim
AU - de Vocht, Joke
AU - Poesen, Koen
AU - Uhlén, Mathias
AU - Anink, Jasper
AU - Mijnsbergen, Caroline
AU - Vergunst-Bosch, Hermieneke
AU - Hübers, Annemarie
AU - Kläppe, Ulf
AU - Rodriguez-Vieitez, Elena
AU - Gilthorpe, Jonathan D.
AU - Hedlund, Eva
AU - Harris, Robert A.
AU - Aronica, Eleonora
AU - van Damme, Philip
AU - Ludolph, Albert
AU - Veldink, Jan
AU - Ingre, Caroline
AU - Nilsson, Peter
AU - Lewandowski, Sebastian A.
N1 - Funding Information: S.A.L. is supported by the Olle Engkvist Byggmästare Foundation (SLS-499431); Ulla-Carin Lindquists Stiftelse för ALS-forskning, Åhléns Foundation (mA2/h17, 203074); the Thierry Latran Foundation (FIB-ALS); and Neuroförbundet. N.S. was supported by the Wellcome Trust (108726/Z/15/Z), Edmond J. Safra Foundation, Lily Safra and UK Dementia Research Institute. We thank the ALS Stichting grant ‘The Dutch ALS Tissue Bank’ (E.A.) and Netherlands Brain Bank (E.H.) for providing ALS tissue samples. We acknowledge the team who helped in the collection of ALS tissue samples (D. Troost, M. de Visser, A.J. van der Kooi and J. Raaphorst). U.K. and C.I. are supported by Björklunds Fund, the Ulla-Carin Lindquist Foundation, Neuro Sweden and SLL Hälsa Medicin och Teknik. E.R.-V. is supported by the Swedish Alzheimer Foundation (Alzheimerfonden), Swedish Dementia Association (Demensfonden), Gun & Bertil Stohne’s Foundation and Gamla Tjänarinnor Foundation. This project has received funding from the European Research Council under the European Union’s Horizon 2020 Research and Innovation Program (grant agreement no. 772376 – EScORIAL) awarded to J.V. R.A.H. is supported by Alltid Litt Sterkere, AlzheimerFonden, Swedish Medical Research Council, Swedish Brain Foundation and the Karolinska Institutet. M.L. was supported by a grant from the Knut and Alice Wallenberg Foundation (2012.0091). This study was also supported by grants to P.N. from the Swedish FTD Initiative funded by the Schörling Family Foundation and the KTH Center for Applied Precision Medicine funded by the Erling-Persson Family Foundation. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België and the KU Leuven funds ‘Een Hart voor ALS’, ‘Laeversfonds voor ALS Onderzoek’ and the ‘Valéry Perrier Race against ALS Fund’. Several authors of this publication are members of the European Reference Network for Rare Neuromuscular Diseases. We also thank K. Hultenby at the Karolinska Institutet’s electron microscopy facility; G. Ella Thorlacius, M.-G. Hong, S. Bergström, J. Yousef, H. Sarlus and A. Manouchehrinia for support with data analysis; and T. Brännström and M. Marklund for assistance with selection and collection of SOD1G93A mouse tissues. S.A.L. thanks the unpaid interns on Erasmus scholarships for their efforts and contributions. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85104433969&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41591-021-01295-9
DO - https://doi.org/10.1038/s41591-021-01295-9
M3 - Article
C2 - 33859435
SN - 1078-8956
VL - 27
SP - 640
EP - 646
JO - Nature medicine
JF - Nature medicine
IS - 4
ER -