A new knock-in mouse model of l-DOPA-responsive dystonia

Abstract

Abnormal dopamine neurotransmission is associated with many different genetic and acquired dystonic disorders. For instance, mutations in genes critical for the synthesis of dopamine, including GCH1 and TH cause l-DOPA-responsive dystonia. Despite evidence that implicates abnormal dopamine neurotransmission in dystonia, the precise nature of the pre- and postsynaptic defects that result in dystonia are not known. To better understand these defects, we generated a knock-in mouse model of l-DOPA-responsive dystonia (DRD) mice that recapitulates the human p.381Q>K TH mutation (c.1141C>A). Mice homozygous for this mutation displayed the core features of the human disorder, including reduced TH activity, dystonia that worsened throughout the course of the active phase, and improvement in the dystonia in response to both l-DOPA and trihexyphenidyl. Although the gross anatomy of the nigrostriatal dopaminergic neurons was normal in DRD mice, the microstructure of striatal synapses was affected whereby the ratio of axo-spinous to axo-dendritic corticostriatal synaptic contacts was reduced. Microinjection of l-DOPA directly into the striatum ameliorated the dystonic movements but cerebellar microinjections of l-DOPA had no effect. Surprisingly, the striatal dopamine concentration was reduced to ∼1% of normal, a concentration more typically associated with akinesia, suggesting that (mal)adaptive postsynaptic responses may also play a role in the development of dystonia. Administration of D1- or D2-like dopamine receptor agonists to enhance dopamine signalling reduced the dystonic movements, whereas administration of D1- or D2-like dopamine receptor antagonists to further reduce dopamine signalling worsened the dystonia, suggesting that both receptors mediate the abnormal movements. Further, D1-dopamine receptors were supersensitive; adenylate cyclase activity, locomotor activity and stereotypy were exaggerated in DRD mice in response to the D1-dopamine receptor agonist SKF 81297. D2-dopamine receptors exhibited a change in the valence in DRD mice with an increase in adenylate cyclase activity and blunted behavioural responses after challenge with the D2-dopamine receptor agonist quinpirole. Together, our findings suggest that the development of dystonia may depend on a reduction in dopamine in combination with specific abnormal receptor responses.

Current Opinions and Areas of Consensus on the Role of the Cerebellum in Dystonia

“…For example, the basal ganglia and dopamine neurotransmission are associated with many dystonic disorders, such as L-DOPA-responsive dystonia, which is caused by defects in enzymes necessary for the synthesis of catecholamines and ameliorated by L-DOPA treatment. In a knock-in mouse model of L-DOPA-responsive dystonia, restoration of catecholamine synthesis in the striatum via striatal L-DOPA administration ameliorates the dystonic movements, but administration of L-DOPA directly to the cerebellum is ineffective [54], demonstrating that the cerebellum is not always central to or even involved in the expression of dystonia. Thus, the many forms and etiologies of dystonia likely reflect the diversity of brain regions and biochemical defects underlying this heterogeneous disorder.…”

Tyrosine Hydroxylase Binding to Phospholipid Membranes Prompts Its Amyloid Aggregation and Compromises Bilayer Integrity

“…Mutations in TH are associated with neurological disorder of TH deficiency (THD)22, with phenotype ranging from mild L-DOPA responsive dystonia (type A)23 to a progressive encephalopathy with L-DOPA-unresponsive parkinsonism (type B)24. Furthermore, it has also been suggested that TH plays a pathogenic role in PD, either through generation of reactive oxygen species (ROS) during catalysis, especially by uncoupled reactions, and/or as a consequence of enzyme dysregulation252627.…”

Mild dopa-responsive dystonia in heterozygous tyrosine hydroxylase mutation carrier: Evidence of symptomatic enzyme deficiency?

“…As in some other recessive disorders, we hypothesize that heterozygosity in TH-DRD could lead to a benign form of a typically severe disease, possibly due to a mild reduction in TH activity. Supporting this hypothesis, a small but significant reduction in striatal levodopa was observed in the post-mortem brain tissue of a heterozygous knock-in mouse model replicating a human TH mutation, as opposed to the profound reduction seen in the homozygous mouse model, demonstrating that the effect may be dependent on gene dosage [6]. Further studies of adult-onset DRD cases without GCH1 mutations may identify similar cases and provide further insights into the genetic spectrum of this condition.…”