Emerging Common Molecular Pathways for Primary Dystonia
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REVIEW Emerging Common Molecular Pathways for Primary Dystonia Mark S. LeDoux, MD, PhD,1 William T. Dauer, MD,2 and Thomas T. Warner, FRCP, PhD3* 1Department of Neurology, University of Tennessee Health Science Center Memphis, Tennessee 38163, USA 2Department of Neurology and Cell & Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA 3Reta Lila Weston Institute for Neurological Research, UCL Institute of Neurology, London, United Kingdom ABSTRACT: The dystonias are a group of English-language publications available on PubMed hyperkinetic movement disorders whose principal cause relating to the genetics and cellular pathology of dysto- is neuron dysfunction at 1 or more interconnected nia was performed. Numerous potential pathogenetic nodes of the motor system. The study of genes and mechanisms have been identified. We describe those proteins that cause familial dystonia provides critical in- that fall into 3 emerging thematic groups: cell-cycle and formation about the cellular pathways involved in this transcriptional regulation in the nucleus, endoplasmic dysfunction, which disrupts the motor pathways at the reticulum and nuclear envelope function, and control of systems level. In recent years study of the increasing synaptic function. VC 2013 Movement Disorder Society number of DYT genes has implicated a number of cell functions that appear to be involved in the pathogene- Key Words: DYT genes; cell cycle; endoplasmic sis of dystonia. A review of the literature published in reticulum; nuclear envelope; synaptic function The dystonias are a heterogeneous group of hyperki- (CNS) damage and the dystonic movements are part netic movement disorders characterized by sustained of a more complex neurological phenotype. involuntary muscle spasms and postures.1 The most The purpose of this review is to summarize the evi- common forms are primary, in which dystonic move- dence, predominantly from the study of genetic forms ments are the only clinical feature and there is no evi- of dystonia, and highlight cellular pathways that are dence of neurodegeneration. In the majority of these important to the genesis of dystonia. In particular, it cases, the cellular processes that lead to functional focuses on areas where there are common themes to abnormalities of neurons, sufficient to disrupt the the cellular pathogenesis. Most of this information finely tuned control of movement, are unknown. comes from study of monogenic primary dystonias However, in recent years the identification of genes and the proteins that the various DYT genes encode. that cause rare monogenic familial dystonia has given The genetic classification of dystonia has subtypes insight into the neurobiology of dystonia and shed DYT 1–25 and includes pure primary dystonias, dys- light on the molecular mechanisms involved. Further tonia-plus syndromes, in which other features such as evidence has come from the study of more complex myoclonus or parkinsonism are present, and paroxys- forms of secondary dystonia, in which there is evi- mal dyskinesias, in which dystonia is often a promi- dence of neurodegeneration or central nervous system nent feature. Table 1 describes the DYT loci, showing key clinical features and information about ------------------------------------------------------------ *Correspondence to: Professor Thomas T. Warner, Reta Lila Weston the protein encoded by the DYT gene. The following Institute of Neurological Studies, UCL Institute of Neurology, 1 Wakefield sections describe the specific forms of primary and Street, London WC1N 1PJ, UK; [email protected] dystonia-plus syndromes for which the gene and pro- Supported by the Dystonia Medical Research Foundation, Tyler’s Hope tein have been identified and studied and that are dis- for a Dystonia Cure and the NINDS (P50 NS038370) (William T. Dauer). cussed in this review. Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the Acknowledments section online. DYT1 Dystonia: TorsinA Received: 14 January 2013; Revised: 3 May 2013; Accepted: 6 May DYT1 dystonia is caused by a heterozygous 3-bp 2013 GAG deletion in the TOR1A gene.2 TorsinA is a 332– 1 Published online in Wiley Online Library (wileyonlinelibrary.com). amino acid protein typical of the AAA (ATPases DOI: 10.1002/mds.25547 associated with a variety of cellular activities) protein 968 Movement Disorders, Vol. 28, No. 7, 2013 DYSTONIA MOLECULAR PATHWAYS TABLE 1. Summary of genes and proteins involved in genetic forms of primary dystonia and dystonia-plus syndromes Locus Designation Clinical features Gene/inheritance Protein Putative functions Pure dystonia DYT1 Chr9q34.11 Early-onset primary Childhood onset dys- TOR1A Autosomal TorsinA AAA1 protein, nuclear dystonia tonia in limb with dominant envelope, ER secre- generalization tory and stress response, regulation of synaptic function DYT2 Early-onset dystonia Adolescent-onset seg- Autosomal recessive Unknown mental or generalized DYT4 Chr19p13.3 Whispering dysphonia Childhood-onset laryn- TUBB4a Autosomal Beta-tubulin 4a Structural cytoskeleton geal abductor dominant protein spasm with cervical dystonia DYT6 Chr 8p11.21 AD early-onset focal Early-onset dystonia THAP1 Autosomal Thanatos-associated Atypical zinc-finger dystonia with prominent cer- dominant domain-containing protein; THAP do- vical and laryngeal apoptosis associ- main is chromatin- involvement ated protein 1 binding factor and regulates transcription DYT7 Chr 8p Familial focal dystonia Adult-onset focal Unknown Autosomal Unknown dystonia dominant DYT13 Chr1p36.32- Familial craniocervical Focal or segmental Unknown Autosomal Unknown p36.13 dystonia dystonia of cranio- dominant cervical region and upper limbs DYT17 Chr 20p11.2- Early-onset AR Early-onset focal dys- Unknown Autosomal Unknown 2q13.12 dystonia tonia progressing to recessive generalized with dysphonia and dysarthria DYT21 Chr 2q14.3- Late-onset dystonia Late-onset multifocal Unknown Autosomal Unknown q21.3 and generalized dominant dystonia DYT23 Chr9q34.11 Cervical dystonia Late-onset primary CIZ1 Autosomal Cip1-interacting zinc Regulation of G1-S cervical dystonia dominant finger protein 1 cell cycle and DNA replication DYT24 Chr11p14.2 Late-onset dystonia Cranial and cervical ANO3 Autosomal Anoctamin 3 Calcium-gated chlo- dystonia dominant ride channel DYT25 Chr18p Cervical dystonia with Predominantly late- GNAL Autosomal Alpha subunit of G Probable interaction local spread onset primary cervi- dominant protein with D1 and adeno- cal dystonia with sine 2A receptors. spread to face Dystonia plus syndromes DYT3 Xq13.1 X-linked dystonia Segmental or general- TAF1 X-linked TATA box-binding pro- Regulation of tran- (Lubag) ized dystonia with tein associated fac- scription initiation parkinsonism tor 1 and cell cycle DYT5/14 Chr2q13.2 Dopa-responsive Dystonia with parkin- GCH1 Autosomal GTP cyclohydrolase 1 Rate-limiting enzyme dystonia sonism, diurnal var- dominant in synthesis of tet- iation, very good rahydrobiopterin, response to L-dopa key cofactor in monoamine synthe- sis; results in defi- cient dopamine synthesis DYT11 Chr7q21.3 Myoclonic dystonia Upper body myoclonic SGCE Autosomal Epsilon-sarcoglycan Cell membrane protein syndrome jerks with dystonia; dominant that may act as responsive to structural platform alcohol for other protein interactions DYT12 Chr19q13.2 Rapid onset dystonia Acute-onset general- ATP1A3 Autosomal Alpha 3 subunit of Subunit of Na/K parkinsonism ized dystonia with dominant Na/K ATPase ATPase on neuronal parkinsonism, ros- membrane trocaudal gradient of symptoms Movement Disorders, Vol. 28, No. 7, 2013 969 LeDOUX ET AL TABLE 1. Continued Locus Designation Clinical features Gene/inheritance Protein Putative functions DYT15 Chr 18p11 Myoclonus dystonia Childhood-onset myo- Unknown Autosomal Unknown clonus with variable dominant dystonia DYT16 Chr2q31.2 DRD and Dystonia-parkinsonism PRKRA Autosomal Protein kinase, inter- PRKRA is activator of parkinsonism with bulbar involve- recessive feron-inducible dou- proteins involved in ment and ble-stranded RNA response to cell bradykinesia dependent activator stress Paroxysmal dystonia DYT8 Chr2q35 Paroxysmal nonkinesi- Attacks of dystonia or MR-1 Autosomal Myofibrillo-genesis Affect neuronal stress genic dyskinesia choreoathetosis. dominant regulator 1 response pathways (PKND) Precipitants: stress, alcohol, fatigue, coffee DYT9 and DYT18 Paroxysmal exercise Dystonia (usually limb) GLUT1 Autosomal Glucose transporter Reduced glucose Chr1p34.2 induced dystonia brought on by exer- dominant type 1 transport to neu- Episodic ataxia cise; ataxia/spastic- rons with unstable ity between attacks metabolic state DYT10 and DYT19 Proxysmal kinesigenic Attacks of dystonia or PRRT2 Autosomal Proline-rich trans- Interacts with SNAP25 Chr16p11.2 choreoathetosis choreoathetosis dominant membrane protein and may affect (PKC) precipitated by sud- 2 synaptic functions/ den movement; neuronal excitability associated with mi- graine and epilepsy DYT20 Chr 2q31 Canadian PKND PKND phenotype Unknown Autosomal Unknown dominant family; these proteins typically function as oligomers associated protein 1) have been widely reported.11,12 and use the energy of ATP hydrolysis for many func- THAP1 is a transcription factor and a member of tions including protein trafficking, membrane fusion, THAP protein family that contains an evolutionarily protein refolding, and degradation.3 The pathogenic conserved zinc-dependent DNA-binding