Milioto C, Carcolé M, Giblin A, Coneys R, Attrebi O, Ahmed M, Harris SS, Lee BI, Yang M, Ellingford RA, Nirujogi RS, Biggs D, Salomonsson S, Zanovello M, de Oliveira P, Katona E, Glaria I, Mikheenko A, Geary B, Udine E, Vaizoglu D, Anoar S, Jotangiya K, Crowley G, Smeeth DM, Adams ML, Niccoli T, Rademakers R, van Blitterswijk M, Devoy A, Hong S, Partridge L, Coyne AN, Fratta P, Alessi DR, Davies B, Busche MA, Greensmith L, Fisher EM, Isaacs AM. 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. Epub 2024 Feb 29 PubMed.
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Director of Neuromuscular Medicine, Cedars-Sinai Medical Center
This represents another advance in C9ORF72 modeling, by placing expression of one of two different artificially engineered DPR proteins (GR or PR) under the control of the endogenous C9ORF72 promoter. Interestingly, the authors found that lower motor neurons were particularly vulnerable in these mice, while in humans, DPR proteins are only rarely detected in spinal motor neurons and their relevance in disease has therefore been questioned (Gomez-Deza et al., 2015).
The jury is still out on whether rodent models will be helpful in predicting which DPRs are pathogenic in human ALS/FTD, as others have also observed differences such as polyGA appearing to be more toxic than polyPR, despite the fact that the PR is typically more toxic in vitro (LaClair et al., 2020).
It is safe to say that none of the existing rodent models appears to be significantly better than the others. Each may represent a piece of the puzzle, and the broad selection of different models now available allows groups to test different therapeutic approaches in an in vivo setting.
References:
Gomez-Deza J, Lee YB, Troakes C, Nolan M, Al-Sarraj S, Gallo JM, Shaw CE. Dipeptide repeat protein inclusions are rare in the spinal cord and almost absent from motor neurons in C9ORF72 mutant amyotrophic lateral sclerosis and are unlikely to cause their degeneration. Acta Neuropathol Commun. 2015 Jun 25;3:38. PubMed.
LaClair KD, Zhou Q, Michaelsen M, Wefers B, Brill MS, Janjic A, Rathkolb B, Farny D, Cygan M, de Angelis MH, Wurst W, Neumann M, Enard W, Misgeld T, Arzberger T, Edbauer D. Congenic expression of poly-GA but not poly-PR in mice triggers selective neuron loss and interferon responses found in C9orf72 ALS. Acta Neuropathol. 2020 Aug;140(2):121-142. Epub 2020 Jun 19 PubMed.
View all comments by Robert BalohAmsterdam UMC, VU University
Vrije Universiteit Amsterdam
VU University Medical Center
We have read the study from Milioto et al. with much interest, because last year we published a clinical study in which we made a similar observation (Gogishvili et al., 2023), namely that while TGF-β1 was increased in dementia compared to controls, it was lower (at normal levels) in the dementia patients with fast cognitive decline.
The aim of our study was to identify CSF proteins biomarkers that predict fast cognitive decline within dementia patients. TGF-β1 was one of the identified markers with the best predictive power. Therefore, we hypothesized that increased levels of TGF-β1 in CSF in dementia might be a protective response to the pathology. The current study supports this hypothesis and demonstrates how this mechanism could work in their C9ORF72 model. Very exciting!
It is also an illustration of the potential of combining results from CSF and experimental studies to better understand the disease mechanisms, and how that could help us to ultimately capture these processes in humans.
References:
Gogishvili D, Vromen EM, Koppes-den Hertog S, Lemstra AW, Pijnenburg YA, Visser PJ, Tijms BM, Del Campo M, Abeln S, Teunissen CE, Vermunt L. Discovery of novel CSF biomarkers to predict progression in dementia using machine learning. Sci Rep. 2023 Apr 21;13(1):6531. PubMed.
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