Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions

摘要: Dystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse it unknown whether their pathogenesis converges on shared pathways. Mutations in THAP1 [THAP (Thanatos-associated protein) domain containing, apoptosis associated protein 1], a ubiquitously expressed transcription factor with DNA binding protein-interaction domains, cause dystonia, DYT6. There unique, neuronal 50-kDa Thap1-like immunoreactive species, Thap1 levels auto-regulated the mRNA level. However, downstream targets neurons, mechanism via which causes dystonia largely unknown. We used RNA-Seq to assay vivo effect of heterozygote C54Y or ΔExon2 allele gene signatures neonatal mouse striatum cerebellum. Enriched pathways ontology terms include eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Synaptic LongTerm Depression, dysregulated genotype tissue-dependent manner. Electrophysiological neurite outgrowth assays were consistent those enrichments, plasticity defects partially corrected salubrinal. Notably, several these recently implicated other inherited including DYT1. conclude that dysfunction may represent point convergence pathophysiology dystonia.