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

被引：55

作者：

Zakirova, Zuchra ^{[1
]}

Fanutza, Tomas ^{[1
]}

Bonet, Justine ^{[1
]}

Readhead, Ben ^{[2
,3
]}

Zhang, Weijia ^{[4
]}

Yi, Zhengzi ^{[4
]}

Beauvais, Genevieve ^{[5
]}

Zwaka, Thomas P. ^{[6
]}

Ozelius, Laurie J. ^{[7
,8
]}

Blitzer, Robert D. ^{[9
,10
]}

Gonzalez-Alegre, Pedro ^{[5
,11
]}

Ehrlich, Michelle E. ^{[1
,2
,3
]}

机构：

[1] Icahn Sch Med Mt Sinai, Dept Neurol, 1 Gustave L Levy Pl, New York, NY 10029 USA

[2] Icahn Sch Med Mt Sinai, Dept Pediat, 1 Gustave L Levy Pl, New York, NY 10029 USA

[3] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, 1 Gustave L Levy Pl, New York, NY 10029 USA

[4] Icahn Sch Med Mt Sinai, Bioinformat Lab, Dept Med, 1 Gustave L Levy Pl, New York, NY 10029 USA

[5] Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA

[6] Icahn Sch Med Mt Sinai, Black Family Stem Cell Inst, New York, NY USA

[7] Massachusetts Gen Hosp, Dept Neurol, 55 Fruit St, Boston, MA 02114 USA

[8] Harvard Med Sch, Dept Neurol, Boston, MA USA

[9] Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, 1 Gustave L Levy Pl, New York, NY 10029 USA

[10] Icahn Sch Med Mt Sinai, Dept Psychiat, 1 Gustave L Levy Pl, New York, NY 10029 USA

[11] Univ Penn, Dept Neurol, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

PLOS GENETICS | 2018年 / 14卷 / 01期

基金：

美国国家卫生研究院;

关键词：

TRANSCRIPTION FACTOR THAP1; LONG-TERM DEPRESSION; SUBTLE MICROSTRUCTURAL CHANGES; IN MOUSE MODEL; SYNAPTIC PLASTICITY; DYT6; DYSTONIA; TRANSLATIONAL CONTROL; EXPRESSION; TORSINA; ACTIVATION;

D O I：

10.1371/journal.pgen.1007169

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 Delta Exon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2 alpha 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.

引用

页数：25