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- Title
Mitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins.
- Authors
Zeballos C., M. Alejandra; Moore, Hayden J.; Smith, Tyler J.; Powell, Jackson E.; Ahsan, Najah S.; Zhang, Sijia; Gaj, Thomas
- 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. TDP43 proteinopathies are a devastating group of neurodegenerative disorders. Here the authors show that RNA-targeting CRISPR effector proteins can be used to mitigate TDP-43 pathology when targeting ataxin-2, a modifier of TDP-43-associated toxicity, and apply this to a mouse model.
- Subjects
CRISPRS; TDP-43 proteinopathies; AMYOTROPHIC lateral sclerosis; FRONTOTEMPORAL dementia; NEURODEGENERATION
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-42147-z