The term dyskinesia broadly refers to an abnormality or impairment of voluntary movement. Dyskinesias include dystonia, chorea, athetosis, ballism, tics, myoclonus, and, according to some definitions, diminished or impaired voluntary movements due to negative motor signs such as ataxia and paresis. Paroxysmal non-kinesigenic dyskinesia (PNKD, DYT8, OMIM #118800) is an autosomal-dominant episodic movement disorder characterized by bouts of hyperkinetic and/or hypokinetic movements precipitated by alcohol, coffee, stress and fatigue. Gain-of-function point mutations (p.A7V, p.A9V or p.A33P) in PNKD encoded by PNKD on Chr. 2q33 are responsible for most cases of familial PNKD. Overall, dystonia, defined as a syndrome of involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements, or abnormal postures, is the foremost involuntary movement manifest by patients with PNKD. After the administration of alcohol or caffeine, mice expressing mutant mouse Pnkd BAC transgenes exhibit severe axial and appendicular dyskinesias with prominent dystonia. It remains unclear if dystonia is truly a network disorder or secondary to isolated dysfunction of a single locus or neuronal population. Similar uncertainties apply to the precise neuroanatomical (e.g., basal ganglia direct pathway, basal ganglia indirect pathway, corticostriatal projections, cerebellar cortex) bases for chorea, athetosis, myoclonus and tics. Our global hypothesis is that isolated dystonia and the dystonic manifestations of PNKD are caused by aberrant cerebellar output due to signaling abnormalities of cerebellar cortex. Conditional mouse models of PNKD (Pnkd) offer the distinct possibility of exposing the functional network pathobiology of dystonia, dyskinesias and paroxysmal disorders of the central nervous system. Paroxysmal neurological disorders are ideal model systems for studying neural networks by allowing for direct comparisons of ictal and inter-ictal states. Conditional mouse models of PNKD could have a profound impact on motor systems and movement disorders research. Therefore, our objectives are to generate novel conditional mouse models of PNKD to provide a platform for hypothesis-driven studies of dystonia and other dyskinesias.
The term dyskinesia broadly refers to an abnormality or impairment of voluntary movement. In humans, dyskinesias can be hereditary or caused by a wide variety of insults to the brain. Our objective is to generate novel mouse models to study the neural circuitry that is responsible for the development of dyskinesias in humans.
| Xiao, Jianfeng; Khan, Mohammad Moshahid; Vemula, Satya et al. (2018) Consequences of Cre-mediated deletion of Ciz1 exon 5 in mice. FEBS Lett 592:3101-3110 |
