Emerging pathways of dystonia pathogenesis: eIF2a and neuroplasticity defects in DYT6

Dystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse and it is unknown whether their pathogenesis converges on shared pathways. Mutations in THAP1, a zinc-finger transcription factor, cause DYT6, but its neuronal targets and functions are unknown. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1C54Y or ?Exon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2a Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic Long Term Depression pathways, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays confirmed the functional significance of those findings. Notably, several of these pathways were recently implicated in other forms of inherited dystonia, including DYT1. We conclude that dysfunction of these pathways may represent a point of convergence on the pathogenesis of unrelated forms of inherited dystonia. Overall design: We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1C54Y or deltaExon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum

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Zakirova Z, Fanutza T, Bonet J, Readhead B, Zhang W, Yi Z, Beauvais G, Zwaka TP, Ozelius LJ, Blitzer RD, Gonzalez-Alegre P, Ehrlich ME