PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

Carmelo Milioto, Mireia Carcolé, Ashling Giblin, Rachel Coneys, Olivia Attrebi, Mhoriam Ahmed, Samuel S. Harris, Byung Il Lee, Mengke Yang, Robert A. Ellingford, Raja S. Nirujogi, Daniel Biggs, Sally Salomonsson, Matteo Zanovello, Paula de Oliveira, Eszter Katona, Idoia Glaria, Alla Mikheenko, Bethany Geary, Evan UdineDeniz Vaizoglu, Sharifah Anoar, Khrisha Jotangiya, Gerard Crowley, Demelza M. Smeeth, Mirjam L. Adams, Teresa Niccoli, Rosa Rademakers, Marka van Blitterswijk, Anny Devoy, Soyon Hong, Linda Partridge, Alyssa N. Coyne, Pietro Fratta, Dario R. Alessi, Ben Davies, Marc Aurel Busche, Linda Greensmith, Elizabeth M .C. Fisher (Lead / Corresponding author), Adrian M. Isaacs (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review


Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.

Original languageEnglish
Pages (from-to)643-655
Number of pages13
JournalNature Neuroscience
Issue number4
Early online date29 Feb 2024
Publication statusPublished - Apr 2024

ASJC Scopus subject areas

  • General Neuroscience


Dive into the research topics of 'PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons'. Together they form a unique fingerprint.

Cite this