Mitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins

M. Alejandra Zeballos C., Hayden J. Moore, Tyler J. Smith, Jackson E. Powell, Najah S. Ahsan, Sijia Zhang and Thomas Gaj ()
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M. Alejandra Zeballos C.: University of Illinois Urbana-Champaign
Hayden J. Moore: University of Illinois Urbana-Champaign
Tyler J. Smith: University of Illinois Urbana-Champaign
Jackson E. Powell: University of Illinois Urbana-Champaign
Najah S. Ahsan: University of Illinois Urbana-Champaign
Sijia Zhang: University of Illinois Urbana-Champaign
Thomas Gaj: University of Illinois Urbana-Champaign

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The TDP-43 proteinopathies, which include amyotrophic lateral sclerosis and frontotemporal dementia, are a devastating group of neurodegenerative disorders that are characterized by the mislocalization and aggregation of TDP-43. Here we demonstrate that RNA-targeting CRISPR effector proteins, a programmable class of gene silencing agents that includes the Cas13 family of enzymes and Cas7–11, can be used to mitigate TDP-43 pathology when programmed to target ataxin-2, a modifier of TDP-43-associated toxicity. In addition to inhibiting the aggregation and transit of TDP-43 to stress granules, we find that the in vivo delivery of an ataxin-2-targeting Cas13 system to a mouse model of TDP-43 proteinopathy improved functional deficits, extended survival, and reduced the severity of neuropathological hallmarks. Further, we benchmark RNA-targeting CRISPR platforms against ataxin-2 and find that high-fidelity forms of Cas13 possess improved transcriptome-wide specificity compared to Cas7–11 and a first-generation effector. Our results demonstrate the potential of CRISPR technology for TDP-43 proteinopathies.

Date: 2023
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DOI: 10.1038/s41467-023-42147-z

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