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Primary Neurons and Differentiated NSC-34 Cells Are More Susceptible to Arginine-Rich ALS Dipeptide Repeat Protein-Associated Toxicity than Non-Differentiated NSC-34 and CHO Cells

ALS Therapy Development Institute, Cambridge, MA 02139, USA
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Int. J. Mol. Sci. 2019, 20(24), 6238; https://doi.org/10.3390/ijms20246238
Received: 18 October 2019 / Revised: 2 December 2019 / Accepted: 9 December 2019 / Published: 11 December 2019
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
A repeat expansion mutation in the C9orf72 gene is the most common known genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In this study, using multiple cell-based assay systems, we reveal both increased dipeptide repeat protein (DRP) toxicity in primary neurons and in differentiated neuronal cell lines. Using flow cytometry and confocal laser scanning microscopy of cells treated with fluorescein isothiocyanate (FITC)-labeled DRPs, we confirm that poly-glycine-arginine (GR) and poly-proline-arginine (PR) DRPs entered cells more readily than poly-glycine-proline (GP) and poly-proline-alanine (PA) DRPs. Our findings suggest that the toxicity of C9-DRPs may be influenced by properties associated with differentiated and aging motor neurons. Further, our findings provide sensitive cell-based assay systems to test phenotypic rescue ability of potential interventions. View Full-Text
Keywords: amyotrophic lateral sclerosis; C9orf72; ALS; dipeptide repeat proteins; arginine-rich; FTD; poly-GR; poly-PR; neurodegeneration; ALS/FTD amyotrophic lateral sclerosis; C9orf72; ALS; dipeptide repeat proteins; arginine-rich; FTD; poly-GR; poly-PR; neurodegeneration; ALS/FTD
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Gill, A.L.; Wang, M.Z.; Levine, B.; Premasiri, A.; Vieira, F.G. Primary Neurons and Differentiated NSC-34 Cells Are More Susceptible to Arginine-Rich ALS Dipeptide Repeat Protein-Associated Toxicity than Non-Differentiated NSC-34 and CHO Cells. Int. J. Mol. Sci. 2019, 20, 6238.

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