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

Zuchra Zakirova, Tomas Fanutza, Justine Bonet, Benjamin Readhead, Weijia Zhang, Zhengzi Yi, Genevieve Beauvais, Thomas P. Zwaka, Laurie J. Ozelius, Robert D. Blitzer, Pedro Gonzalez-Alegre, Michelle E. Ehrlich

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere1007169
JournalPLoS Genetics
Volume14
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Fingerprint

Dystonia
mutation
Mutation
protein
gene
neurons
assay
Genes
neurites
genes
proteins
muscle contraction
apoptosis
assays
cerebellum
pathophysiology
automobiles
contraction
defect
plasticity

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

Cite this

Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions. / Zakirova, Zuchra; Fanutza, Tomas; Bonet, Justine; Readhead, Benjamin; Zhang, Weijia; Yi, Zhengzi; Beauvais, Genevieve; Zwaka, Thomas P.; Ozelius, Laurie J.; Blitzer, Robert D.; Gonzalez-Alegre, Pedro; Ehrlich, Michelle E.

In: PLoS Genetics, Vol. 14, No. 1, e1007169, 01.01.2018.

Research output: Contribution to journalArticle

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 2018, 'Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions', PLoS Genetics, vol. 14, no. 1, e1007169. https://doi.org/10.1371/journal.pgen.1007169
Zakirova, Zuchra ; Fanutza, Tomas ; Bonet, Justine ; Readhead, Benjamin ; Zhang, Weijia ; Yi, Zhengzi ; Beauvais, Genevieve ; Zwaka, Thomas P. ; Ozelius, Laurie J. ; Blitzer, Robert D. ; Gonzalez-Alegre, Pedro ; Ehrlich, Michelle E. / Mutations in THAP1/DYT6 reveal that diverse dystonia genes disrupt similar neuronal pathways and functions. In: PLoS Genetics. 2018 ; Vol. 14, No. 1.
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