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

PLoS Genet. 2018 Jan 24;14(1):e1007169. doi: 10.1371/journal.pgen.1007169. eCollection 2018 Jan.

Abstract

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 [THAP (Thanatos-associated protein) domain containing, apoptosis associated protein 1], a ubiquitously expressed transcription factor with DNA binding and protein-interaction domains, cause dystonia, DYT6. There is a unique, neuronal 50-kDa Thap1-like immunoreactive species, and Thap1 levels are auto-regulated on the mRNA level. However, THAP1 downstream targets in neurons, and the mechanism via which it causes dystonia are largely unknown. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1 C54Y or ΔExon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic LongTerm Depression, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays were consistent with those enrichments, and the plasticity defects were partially corrected by salubrinal. 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 in the pathophysiology of several forms of inherited dystonia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis Regulatory Proteins / genetics*
  • Cells, Cultured
  • DNA-Binding Proteins / genetics*
  • Dystonia / genetics*
  • Humans
  • K562 Cells
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation*
  • Nerve Net / metabolism
  • Nerve Net / physiology*
  • Neuronal Plasticity / genetics
  • Neurons / physiology*
  • Nuclear Proteins / genetics*

Substances

  • Apoptosis Regulatory Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • THAP1 protein, human
  • THAP1 protein, mouse