Genetic animal models of dystonia: Common features and diversities
Introduction
More than 3 million people worldwide suffer from dystonia (Jinnah and Hess, 2008), the third most common movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation (Albanese et al., 2013). It can present isolated or in combination/co-occurrence with a large number of other neurological disorders, ranging from ataxia to Parkinson's disease (PD). Classification of the different representations of dystonia is challenging and has been modified extensively over the last 40 year (Albanese et al., 2013, Fahn, 2011). Current classification separates dystonia disorders by clinical characteristics (Axis I, age at onset, body distribution, temporal pattern and associated features) and etiology (Axis II, nervous system pathology, inherited or acquired).
It was estimated that for one third of cases a causative factor has been identified, whereby hereditary Dyt1 dystonia accounts for up to 90% of the early onset dystonia cases (Spatola and Wider, 2012). More than 20 different gene mutations, currently designated as DYT1-25 (Lohmann and Klein, 2013, Moghimi et al., 2013), related to dystonia are now isolated and have been extensively reviewed recently (Fuchs and Ozelius, 2011, Lohmann and Klein, 2013, Ozelius et al., 2011, Spatola and Wider, 2012). For more than half of these genes encoded proteins were identified (Fig. 1) and found to be involved in a broad range of functions, including dopamine signaling, protein chaperoning, transcriptional regulation or transporter proteins (Ledoux et al., 2013, Lohmann and Klein, 2013, Ozelius et al., 2011, Spatola and Wider, 2012). Penetrance of the most common subtype of inherited dystonia, DYT1, is not complete (Ghilardi et al., 2003), indicating the importance of environmental or additional genetic factors in pathophysiology. Such factors may increase probability of developing the symptoms or represent compensatory mechanisms in asymptomatic carriers, similar to what is described in some genetic forms of PD and PD animal models (Chesselet and Richter, 2011).
Similar interactions of gene mutations, genetic background and environmental factors may contribute to forms of late onset dystonia, which are generally more common. Recent genome wide association studies aimed to identify large effect-size risk loci in cervical dystonia suggested the involvement of a sodium leak channel (Mok et al., 2013). Prevalence of dystonia will further increase in association with age related diseases like PD, due to the prolongation of life span. Currently PD already affects more than 2% of the population above 65 years of age. In PD, a retrospective observational study showed that a third of patients had a deformity of their limbs, neck, or trunk, which are refractory to L-DOPA treatment and can present early in PD disease progression (Doherty et al., 2011). Furthermore, dystonia can present together or in sequence with PD (Spatola and Wider, 2012). In fact, in the population over 50 years of age dystonia can be defined as a common neurological disorder, placing it among the top disorders to impact quality of life and health care costs in aging societies (Phukan et al., 2011). Furthermore, dystonia can be acquired through medications, toxins, trauma, brain tumors or viral infection (Breakefield et al., 2008).
Unfortunately, pharmacological treatment of the different clinical types of dystonia is insufficient or ineffective in most cases and largely based on empirical, rather than scientific rationale (Jankovic, 2009). However, with the recent identification of the gene products of a number of mutations which cause dystonia (Fuchs and Ozelius, 2011, Lohmann and Klein, 2013), and the development of multiple rodent models, pathophysiological studies and pre-clinical drug screens become more feasible (Jinnah and Hess, 2008, Klein et al., 2011). A growing number of animal models of dystonia created on the basis of recently identified gene mutations that cause dystonia in humans, together with established rodent models that express dystonic postures or movements can be immensely helpful to uncover risk factors and pathophysiology of dystonia. The urgent need for improved and novel treatments demands further characterization of these models. However, similar to other disorders extensively modeled in animals, it cannot be expected that one animal model will encompass all features of such a complex and diverse disorder. Instead the current models should be viewed as tools to study and treat specific facets of the disorder.
Here, we will present an overview of current models organized by the features of dystonia they are required to express. In the first chapters we focus on motor dysfunction, dystonic postures and non-motor dysfunction by first describing the symptoms in human patients followed by the respective representation in animal models. Next we present current knowledge on neuropathology and pathophysiology in human dystonia, again discussing how this is reflected in respective animal models. This organization will aid readers to identify models which represent a specific aspect of the disease and could for example be used to develop therapeutic intervention. In our detailed description of the models for each chapter, we will focus on rodent models as first-line tools for the identification of drug targets and preclinical drug testing. In the final sections we will summarize and discuss the current invertebrate genetic models and pharmacological models in rodents and primates. Most relevant genetic models are described in detail in the text and in Table 1. Additional genetic and toxin or drug induced rodent models are briefly mentioned in the text and details are summarized in Table 1.
Section snippets
Motor dysfunction and dystonic postures
Dystonia is by definition a collection of symptoms which express mainly as hyperkinetic motor dysfunction including dystonic postures and movements, which at the peak of expression often overflow beyond primarily involved body region. Dystonic symptoms can occur constantly or paroxysmal, can get progressively worse, remain unchanged or alleviate with age. Postures may include extremities, the head or the body axis, whereas dystonic movements can develop out of a specific daily use or overuse of
Anxiety, cognitive impairments and other non-motor symptoms
Apart from the above mentioned motor learning impairments and sensory abnormalities, dystonia patients with or without known gene mutations can develop a broad range of non-motor symptoms (reviewed in Stamelou et al., 2012). These symptoms are understudied and often not adequately diagnosed and treated in patients. The impact on quality of life indicates the importance of taking non-motor symptoms into account when developing and evaluating new treatments for dystonia (Kuyper et al., 2011).
Basal ganglia dysfunction
The neuropathological mechanisms of dystonia are largely unclear; however, there is increasing evidence of neuronal dysfunction and specific brain regions involved (as recently reviewed by Neychev et al., 2011, Ozelius et al., 2011). There is evidence from inherited and acquired dystonia that dysfunctions of the basal ganglia can play a pivotal role in development of dystonia, which has been confirmed in animal models. Abnormal striatal output may lead in some etiologies to dysfunction in the
Cerebellar dysfunction
There is ample evidence of involvement of the cerebellum in etiology and pathophysiology of dystonia, however, it is disputed if it can play a primary role or generally exaggerates an ongoing pathogenesis which originates in the basal ganglia. Experimental murine or primate models with injections of toxins or electrical stimulation in the cerebellum support that such alterations can produce dystonic like movements and secondary alterations in other brain structures (Hoshi et al., 2005, Neychev
Inclusion bodies or other pathomorphological changes
Recent evidence from pathological examinations and imaging studies support pathomorphological changes in brain of dystonia patients (reviewed in Lehericy et al., 2013, Standaert, 2011). Microscopic inspection of the substantia nigra revealed, that the pigmented neurons appeared to be larger and more densely packed in DYT1 dystonia brains than in most normal brains (Rostasy et al., 2003). In four cases of genetically confirmed DYT1 dystonia McNaught et al. (2004) found inclusions in neurons of
Neurophysiology: abnormal striatal synaptic plasticity in dystonia
Abnormal neuroplasticity may represent a common feature of pathophysiology in different types of dystonia and therefore provide an attractive target for therapeutic intervention. Neuroplasticity as term is used to describe the ability of the nervous system to morphologically and/or biochemically change neural pathways and synapses in response to information received. Extrinsic input gated by the sensory system as well as intrinsic input of the specific genetics interplay with complex modifiers
How to choose a model for drug testing: current options and limitations
Expression of a behavioral phenotype (face validity) seems indispensable as prerequisite for the use of animal models in therapy development for dystonia, despite the recent reports on pathomorphological and functional alterations in patients and models. Underlying pathomorphological changes that can be found in both the human patient and in the models are subtle and not consistent across different types of dystonia or models, making their use as endpoint to translate drug effects from rodent
Invertebrate and zebrafish genetic models of dystonia: insights and outlook
Understanding the underlying pathogenesis of different forms of dystonia is essential for the development of efficacious therapeutics. One research avenue is the characterization of identified gene products for the genes associated with dystonia. Their physiological function as well as the impact of specific mutations which can lead to loss of function and/or gain of toxic function of the corresponding protein can be efficiently studied in invertebrate models with short generation times and
Pharmacologic and toxin-induced models of dystonia: a summary on current strategies
Toxins or pharmaceutics applied systemically or stereotactically into different brain regions have been used to induce dystonic features in animals. This has led to confirmation that disturbance of basal ganglia and cerebellar function among other brain regions can result in dystonia and has allowed testing of therapeutic strategies. Among others kainac acid injection into the cerebellum (Alvarez-Fischer et al., 2012, Pizoli et al., 2002), system injection of 3-nitropropionic acid (3-NP) (
Conclusion and perspectives
Models of dystonia have been differentiated in symptomatic (face validity predominant, e.g. spontaneous mutants) versus etiological (construct validity predominant, e.g. DYT1 transgenics) models (Oleas et al., 2013, Wilson and Hess, 2013). This simplified classification is a response to the current lack of models which have been engineered based on etiology and express classical features of dystonia. Clearly, in dystonia the current rapid gain of knowledge of human genetics will lead to further
Authors’ contribution
FR wrote the first draft with input from AR and prepared Figures and Tables. AR modified the final version.
Conflict of interest
The authors have no conflict of interest regarding the content of this manuscript.
Acknowledgments
Studies described in this review were supported by DFG grants RI 845-1/1-3 to AR and by the Dystonia Medical Research Foundation. We thank Anke Hermann for technical assistance in TOR1A qPCR and Dr. Svenja Sander for the video material.
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