International meeting of the French society of neurology & SOFMA 2018Dystonia: Are animal models relevant in therapeutics?
Introduction
More than three million people worldwide suffer from dystonia [1], [2], a term that represents a heterogeneous group of disorders with a variable age of onset (in either childhood or adulthood) and which etiologically may have diverse causes; while genetic and acquired forms are now recognized, most cases are idiopathic [3]. Symptoms can differ significantly in severity, affecting one muscle, a group of muscles or the entire body [4]. However, all dystonias are characterized by an inability to select the correct motor patterns needed to perform specific movements and postures. Muscle activity initiates involuntary movements, especially during maintenance of postures, and then spreads to muscles that are usually not involved in that specific action [5]. Despite the high incidence of dystonia, only a few strictly symptomatic treatments are available, including both pharmacological and surgical approaches; these are expected to ameliorate involuntary movements, correct abnormal postures, relieve pain, prevent contractures and improve quality of life.
However, the development of better therapeutic strategies has been limited by our lack of understanding of the etiology and pathogenesis of dystonia, although significant steps have been taken over the last two decades towards better knowledge of the disease pathogenesis. Genetics has been highly successful in the identification of the numerous causative genes of different forms of monogenic dystonia, thereby providing novel insights to help explore the pathophysiology of these disorders [6], [7], [8]. In addition, functional neuroimaging studies have provided evidence that the anatomical substrates of dystonia are complex, fueling the concept of dystonia as a network disorder, involving both basal ganglia-thalamocortical and cerebello-thalamocortical networks, rather than an isolated dysfunction affecting only one region of the brain [9], [10], [11].
Dystonia research can benefit from animal models in the search for novel pathogenic mechanisms and for testing new therapeutic approaches to well-characterized processes. Yet, the fundamental questions now drawing the attention of the scientific community are how the currently available and future models might be able to recapitulate the human condition, and how predictive might they be of the successful translation of drug model findings applied for clinical purposes.
Three general criteria are now used to determine how relevant an animal model is to diseases in humans:
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face validity of a model is its ability to reproduce the motor behavioral abnormalities observed in human disease;
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construct validity compares the pathophysiological mechanisms reported in human conditions and animal models;
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predictive validity refers to the correspondence of efficacy with a given therapeutic approach.
Every model may be able to fulfill one or more types of validity, although this is not necessarily required, as every model can certainly contribute towards building a larger body of evidence to improve our understanding of disease mechanisms.
Section snippets
Overview of preclinical models in dystonia research
Over the last decade, there has been a sharp increase in the number of dystonia animal models being developed. Selection of a particular model system largely depends on the specific hypotheses and overall goals of the experiment: studies in vitro are often restricted to questions of biochemistry and cell biology [12], whereas mammalian models are often essential for evaluating the efficacy of candidate drugs and devices that target specific receptors and/or structures in the brain. Thus, the
Experimental strategies for new treatments
Detailed characterizations of the currently available animal models of dystonia and the development of new ones hold promise of a better understanding of the pathophysiology of these disorders and the identification of novel treatments. Indeed, several strategies can now be put in place to identify new therapeutic agents while improving existing therapies and identifying new possible targets [40]. However, it should be borne in mind that our ability to detect clinically significant benefits in
Conclusion and future perspectives
Over the last several decades, animal research has provided invaluable information on the biochemical and cellular processes involved in the pathophysiology of human dystonia. In addition, despite some clear limitations such as the difficulty of devising models of both motor and non-motor features, rodent and non-human primate models nonetheless appear to be essential for bridging the translational gap between preclinical and clinical research. However, as no model has yet fulfilled every
Disclosure of interest
The authors declare that they have no competing interest.
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Dystonia
2022, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, Second EditionModels of dystonia: an update
2020, Journal of Neuroscience MethodsCitation Excerpt :Indeed, more than 20 DYT loci have been designated, and accordingly, several genes identified. A comprehensive review of all dystonia models available is beyond the scope of this short survey, and we refer the reader to other excellent reviews for more exhaustive, recent descriptions (Meringolo et al., 2018; Oleas et al., 2013; Pappas et al., 2014). Currently, many genes causative of distinct forms of monogenic dystonia have been identified (Jinnah and Sun, 2019; Lohmann and Klein, 2013; Marras et al., 2016; Verbeek and Gasser, 2016), however, to date, cellular pathomechanisms underlying most dystonias are largely unknown, and it also remains to be established whether different forms of dystonia may share common mechanisms.
Advances in molecular and cell biology of dystonia: Focus on torsinA
2019, Neurobiology of DiseaseCitation Excerpt :A major drawback is the animal models that genetically replicate the human disease do not exhibit dystonia. A matter of debate in the dystonia field for years, rodents are clearly a helpful system to study torsinA biology, but less valuable to mirror the genotype-phenotype correlation observed in humans (Meringolo et al., 2018; Jinnah et al., 2008). How could we determine which of the biological pathways dysfunctional in DYT1 models are related to dystonia?
Hyperkinetic Rat Model Induced by Optogenetic Parafascicular Nucleus Stimulation
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