ReviewMolecular pathways in dystonia
Introduction
The dystonias are a heterogenous group of movement disorders in which affected individuals develop sustained, involuntary muscle contractions and twisted postures (Geyer and Bressman, 2006). These deficits may be the sole clinical manifestation or occur as secondary symptoms due to other underlying disease processes, drug/toxin exposure or brain injury (Geyer and Bressman, 2006, Fahn, 1988). Dystonia is generally classified based on somatic distribution of symptoms (focal, segmental, or generalized), age of disease onset (early or late), and etiology (primary or secondary). An alternative scheme, based on Human Genome Organization (HUGO) nomenclature, designates the monogenic dystonias as numbered subtypes, DYT1–DYT20, according to the order in which clinical features and/or genetic mapping were first reported. This list of 20 subtypes currently includes (1) pure dystonias; (2) dystonia-plus syndromes in which other manifestations, such as parkinsonism or myoclonus, are also present; and (3) paroxysmal dyskinesias, in which dystonia may be an additional feature (de Carvalho Aguiar and Ozelius, 2002, Tanabe et al., 2009, Müller, 2009, Brüggemann and Klein, 2010).
The physiological hallmark of all of these syndromes is the simultaneous contraction of agonist and antagonist muscles, which is believed to reflect a dysfunction in CNS regions controlling movement. The precise nature of this dysfunction is unclear, although a general consensus is that it may involve imbalances in neurotransmission within certain circuits, particularly in the basal ganglia, sensorimotor cortex, brainstem, and cerebellum (for review see Breakefield et al., 2008, Quartarone et al., 2008). How different dystonia-related gene products impact neurotransmission remains unresolved, and it is likely that specific pathogenic mechanisms differ among dystonia subtypes. Nevertheless, studies of dystonia pathogenesis have frequently focused on a few common themes, including neurodevelopmental abnormalities, altered pre- and/or post-synaptic activity, and neurotoxicity. However, the latter is generally not considered a significant factor in primary dystonia, which is distinguished by a lack of any characteristic neuropathology.
Since primary dystonia constitutes a chronic dysfunction, rather than a neurodegenerative disease, the likelihood is increased that it may eventually be possible to correct the underlying defect(s) once they are fully elucidated. Despite great progress in identifying genetic loci linked to dystonia, it has been difficult to translate that information into a clear understanding of the affected CNS pathways and the functional consequences of specific mutations. Of the 20 current dystonia subtypes, 10 have been linked to mutations in genes encoding novel or previously known proteins (Table 1). In some cases, the effects of the mutations are well understood, as with two genes responsible for DYT5 which encode tyrosine hydroxylase and GTP-cyclohydrolase, both of which are required for dopamine biosynthesis (Segawa, 2000). For other dystonia genes, the function of the encoded proteins and effects of disease mutations are less clear. Understanding how these gene mutations individually culminate in dystonia is obviously critical to designing therapeutic strategies. Yet equally important is the identification of common molecular pathways that may be dysregulated in multiple dystonia subtypes. Given that individual forms of dystonia may be relatively rare, finding common pathways to be targeted for intervention would increase the likelihood that a new treatment approach might have widespread therapeutic benefit.
In this review we discuss recent advances in the biology of three forms of hereditary dystonia: DYT1, DYT6, and DYT16. Compared to DYT1, studies of DYT6 and DYT16 are still in their infancies, with relatively little known about the causative gene products and no animal models yet established for probing disease mechanisms. Yet the limited data that have recently emerged provide initial clues as to potential interactions between these proteins and/or their possible interrelationships to molecular pathways. Here we review these possibilities, highlighting how these proteins may be related to each other in the context of dopamine signaling, transcriptional regulation, and stress responses in the endoplasmic reticulum.
Section snippets
Genes, proteins, and clinical phenotypes
As the name implies, the first form of dystonia to be associated with a genetic basis was DYT1, which is caused by a heterozygous, 3-bp deletion that removes one of two adjacent trinucleotides (904_906delGAG/907_909delGAG) in TOR1A (Ozelius et al., 1997). Four other mutations have since been identified in TOR1A (Leung et al., 2001, Kabakci et al., 2004, Zirn et al., 2008, Calakos et al., 2010), although it is unclear whether all are in fact pathogenic (Fig. 1A). The DYT6 gene was recently
Dopaminergic signaling
While it is likely that multiple neurotransmitter systems contribute to dystonia pathogenesis in different ways, the pathway most extensively studied to date is dopamine (DA). Multiple lines of evidence suggest that dysfunctions in DA signaling can induce dystonic symptoms (for review, see Wichmann, 2008, Tanabe et al., 2009). In human studies, this hypothesis is supported by reports that dystonia may be associated with: (1) mutations in genes encoding proteins critical for DA biosynthesis,
Transcriptional regulation
Although the interaction between THAP1 and Par-4 is intriguing in light of an hypothesized effect on D2R, functional analyses of THAP1 have thus far focused on its role in transcription. The conserved N-terminal THAP domain is a zinc-coordinating module that binds a specific DNA sequence, termed THABS (for THAP DNA-Binding Sequence) (Clouaire et al., 2005). Overexpression and/or silencing of THAP1 in cultured cells altered transcription of a number of genes, including ones known to regulate
Endoplasmic reticulum stress
Given that the bulk of torsinA appears to reside within the ER lumen, numerous studies have attempted to define its role and/or a functional consequence of torsinAΔE in this compartment. Although multiple theories have been advanced, they can be distilled into three, non-mutually exclusive hypotheses: (1) torsinAΔE is a misfolded protein which triggers an ER stress response; (2) torsinA acts as a classical chaperone, assisting in the folding of client proteins that move through the secretory
Seeking common themes in dystonia neurobiology
Translational research in the dystonias has generally lagged behind efforts for other neurologic diseases for multiple reasons. Although collectively the dystonias represent a common movement disorder, estimated as the third most prevalent behind Parkinson's disease and essential tremor, individual forms of dystonia, particularly the monogenic ones, are relatively rare and probably caused by different molecular etiologies. In most cases, these etiologies are poorly understood, thereby limiting
Acknowledgments
The authors gratefully acknowledge Dr. John R. Engen, for assistance with structural modeling of THAP1, Ms. Emily Mills and Millstone Design (www.millstone.com) for preparation of Fig. 2, Fig. 4, and Ms. Suzanne McDavitt, for the skilled editorial assistance with this manuscript. This work supported by NIH/NINDS grants NS064450 (DCB), NS069973 (DCB), NS037409 (XOB, NS), as well as grants from Tyler's Hope for a Dystonia Cure, Inc. (DCB) and the Dystonia Medical Research Foundation (FCN).
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