Emerging common molecular pathways for primary dystonia

Abstract

The dystonias are a group of hyperkinetic movement disorders whose principal cause is neuron dysfunction at 1 or more interconnected nodes of the motor system. The study of genes and proteins that cause familial dystonia provides critical information about the cellular pathways involved in this dysfunction, which disrupts the motor pathways at the systems level. In recent years study of the increasing number of DYT genes has implicated a number of cell functions that appear to be involved in the pathogenesis of dystonia. A review of the literature published in English-language publications available on PubMed relating to the genetics and cellular pathology of dystonia was performed. Numerous potential pathogenetic mechanisms have been identified. We describe those that fall into 3 emerging thematic groups: cell-cycle and transcriptional regulation in the nucleus, endoplasmic reticulum and nuclear envelope function, and control of synaptic function. © 2013 Movement Disorder Society.

Keywords: DYT genes; cell cycle; endoplasmic reticulum; nuclear envelope; synaptic function.

Figure 1

G1/S cell-cycle checkpoint and dystonia. Dystonia-associated proteins are shaded red. Indirect, multi-step and putative pathways are denoted with hashed lines. In general, arrows indicate excitatory interactions and stops mark inhibitory interactions. However, some relationships are non-linear and the result of combinatorial actions of heteromeric complexes and post-translational modifications. +p, phosphorylation. ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related protein; CDC25A, cell division cycle 25 homolog A; CDK2, cyclin-dependent kinase 2; CDK4, cyclin-dependent kinase 4; CDK6, cyclin-dependent kinase 6; CDKN1A, p21/WAF1 or cyclin-dependent kinase inhibitor 1; CHK1, checkpoint kinase 1; CIZ1, Cip1-interacting zinc finger protein; E2F, transcription factor E2F; G1 Phase, Gap 1 phase of the cell cycle; p53, protein 53; R, restriction point; Rb, retinoblastoma protein; SMAD2, mothers against decapentaplegic homolog 2; SMAD3, mothers against decapentaplegic homolog 3; S Phase, synthesis phase. TAF1, transcription initiation factor TFIID subunit 1; TFDP1, transcription factor Dp1; TGFβ, transforming growth factor β.

Figure 2

Potential interactions of torsinA and THAP1 at the nuclear envelope.

Figure 3

Schematic diagram of synapse indicating potential impact of proteins whose mutant forms cause dystonia. 1A: presynaptic terminal showing interaction of torsinA, DAT and mutations in GCH1 and TH on synaptic vesicle recycling, dopamine uptake and synthesis respectively. 1B: postsynaptic terminal. TorsinA and THaP1 may affect dopamine receptor expression of function. D2R and A2AR function may be influenced by these proteins or directly by GNAL influencing PKA phosphorylation and promoting delivery of GluA1-containing AMPARs to extrasynaptic pools increasing their availability for subsequent synaptic recruitment upon LTP induction and NMDAR activation. Calcium influx through synaptic NMDARs is endogenously facilitated by A_2AR, but it can also be inhibited by activation of D₂R through PKA-dependent mechanisms. α, β, γ: subunits of G protein, DA: Dopamine, D2: Dopamine type2 receptor, D1: Dopamine type 1 receptor, GCH1: GTPcyclohydrolase 1, GNAL: stimulatory a subunit of G protein, TH: tyrosine hydroxylase, ER: endoplasmic reticulum, A2AR adenosine 2 receptor, AMPAR: AMPA receptor, NMDAR: NMDA receptor.