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 Udine; Deniz 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; Adrian M Isaacs

doi:10.1038/s41593-024-01589-4

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

Nat Neurosci. 2024 Apr;27(4):643-655. doi: 10.1038/s41593-024-01589-4. Epub 2024 Feb 29.

Authors

Carmelo Milioto^{1

2}, Mireia Carcolé^{1

2}, Ashling Giblin^{1

2

3}, Rachel Coneys^{1

2}, Olivia Attrebi^{1

2}, Mhoriam Ahmed⁴, Samuel S Harris¹, Byung Il Lee¹, Mengke Yang¹, Robert A Ellingford¹, Raja S Nirujogi^{5

6}, Daniel Biggs⁷, Sally Salomonsson^{1

2}, Matteo Zanovello⁴, Paula de Oliveira^{1

2}, Eszter Katona^{1

2}, Idoia Glaria^{1

2

8}, Alla Mikheenko^{1

2

4}, Bethany Geary^{5

6}, Evan Udine⁹, Deniz Vaizoglu^{1

2}, Sharifah Anoar³, Khrisha Jotangiya^{1

2}, Gerard Crowley¹, Demelza M Smeeth^{1

2}, Mirjam L Adams^{1

2}, Teresa Niccoli³, Rosa Rademakers^{10

11}, Marka van Blitterswijk⁹, Anny Devoy¹², Soyon Hong¹, Linda Partridge³, Alyssa N Coyne^{13

14}, Pietro Fratta^{4

15}, Dario R Alessi^{5

6}, Ben Davies^{7

16}, Marc Aurel Busche¹, Linda Greensmith^{4

15}, Elizabeth M C Fisher^{17

18}, Adrian M Isaacs^{19

20

21}

Affiliations

¹ UK Dementia Research Institute, University College London, London, UK.
² Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
³ UCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.
⁴ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
⁵ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
⁶ Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
⁷ Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
⁸ Research Support Service, Institute of Agrobiotechnology, CSIC-Government of Navarra, Mutilva, Spain.
⁹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
¹⁰ VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
¹¹ Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
¹² UK Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
¹³ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁴ Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁵ UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, London, UK.
¹⁶ Francis Crick Institute, London, UK.
¹⁷ Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK. elizabeth.fisher@ucl.ac.uk.
¹⁸ UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, London, UK. elizabeth.fisher@ucl.ac.uk.
¹⁹ UK Dementia Research Institute, University College London, London, UK. a.isaacs@ucl.ac.uk.
²⁰ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. a.isaacs@ucl.ac.uk.
²¹ UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, London, UK. a.isaacs@ucl.ac.uk.

Abstract

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.

MeSH terms

Amyotrophic Lateral Sclerosis* / metabolism
Animals
C9orf72 Protein / genetics
C9orf72 Protein / metabolism
DNA Repeat Expansion / genetics
Dipeptides / metabolism
Drosophila
Extracellular Matrix / metabolism
Frontotemporal Dementia* / pathology
Humans
Induced Pluripotent Stem Cells* / metabolism
Mice
Motor Neurons / metabolism
Transforming Growth Factor beta1

Substances

Transforming Growth Factor beta1
C9orf72 Protein
Dipeptides
C9orf72 protein, human

Abstract

MeSH terms

Substances

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