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Models of TDP-43 Proteinopathy in ALS / FTD and RNA targeting using CRISPR / Cas9


Misregulation of RNA processing is a major component of the related neurodegenerative diseases Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. TDP-43 is an RNA binding protein and the primary pathological finding in both diseases. Post-translational modification of TDP-43 by direct S-nitrosylation of cysteines 173 and 175 leads to disulfide bond formation and loss of solubility in ALS / FTD models. Further, TDP-43 aggregation may be able to induce nitrosative stress within the cell, leading to further loss of solubility. We present models of TDP-43 aggregation that demonstrate TDP-43 is capable of propagating between cells quantifiably, spreading disease-associated aggregates. C9orf72 is the most common genetic cause of ALS / FTD, and here we establish a CRISPR / Cas9 technology capable of tracking and degrading RNA foci found in in myotonic dystrophy and C9 ALS. Our findings provide a novel framework for therapeutics targeted at TDP-43 aggregation and RNA toxicity.

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