biostudies-literatureUnknownZeballos C MANIBIB NIH HHSNINDS NIH HHSNIGMS NIH HHSThe 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 <i>in vivo</i> 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 neurobioRxiv : the preprint server for biology2023.04.07.536072https://www.ebi.ac.uk/biostudies/studies/S-EPMC10104115biostudies-literatureMitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins.PMC10104115U01 NS122102T32 EB019944R01 GM141296R01 NS123556Gaj TZeballos C MAAhsan NSPowell JESmith TJZhang SMoore HJfalseMitigating a TDP-43 proteinopathy by targeting ataxin-2 using RNA-targeting CRISPR effector proteins.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 <i>in vivo</i> 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 neuro2023-01-01T00:00:00Z2023 Aug2025-04-04T10:21:53.418Z2025-02-19T02:38:21.618ZS-EPMC101041153706617410.1101/2023.04.07.536072