Journal Article

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

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

2024

Overview

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. C9orf72 ALS/FTD polyGR and polyPR knock-in mice show cortical hyperexcitability and motor neuron loss accompanied by an increase in extracellular matrix proteins in the spinal cord that is conserved in patient iPS cell-derived neurons and is neuroprotective.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378/1689/1285 / 631/378/1689/364 / Amyotrophic lateral sclerosis / Amyotrophic Lateral Sclerosis - metabolism / Animal Genetics and Genomics / Animal models / Animals / Behavioral Sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / C9orf72 Protein - genetics / C9orf72 Protein - metabolism / Cell death / Dementia disorders / Dipeptides - metabolism / DNA Repeat Expansion - genetics / Drosophila / Extracellular matrix / Extracellular Matrix - metabolism / Frontotemporal dementia / Frontotemporal Dementia - pathology / Humans / Induced Pluripotent Stem Cells - metabolism / Mice / Motor neurons / Motor Neurons - metabolism / Neurobiology / Neurodegeneration / Neurons / Neuroprotection / Neurosciences / Pluripotency / Proteins / Proteomics / Spinal cord / Stem cells / Transforming Growth Factor beta1 / Transforming growth factor-b1