Tic12, a 12-kDa essential component of the translocon at the inner envelope membrane of chloroplasts in Arabidopsis.

The complexes translocon at the outer envelope membrane of chloroplasts and translocon at the inner envelope membrane of chloroplasts (TIC) mediate preprotein translocation across the chloroplast outer and inner envelope membranes, respectively. Tic20, Tic56, Tic100, and Tic214 form a stable one-megadalton TIC whose function is essential for Arabidopsis thaliana and Chlamydomonas reinhardtii. Tic20 plays a central role in preprotein translocation by forming a protein-conducting channel. Tic56, Tic100, and Tic214 are also indispensable for TIC function, but whether other components are required for this process remain unclear. Here, we demonstrate that a 12-kDa protein named Tic12 is part of the TIC in A. thaliana and participates in preprotein translocation across the inner envelope membrane. Tic12 was tightly associated with the TIC but disassociated under high-salt conditions in combination with Triton X-100. Site-specific UV crosslinking experiments revealed that Tic12 and Tic20 directly interact with the transit peptide of a translocating preprotein. The tic12 null mutants are albino and seedling lethal, similar to the other tic null mutants. Tic12 and Tic20 were also involved in preprotein translocation in (Pisum sativum) pea chloroplasts. Thus, Tic12 is an essential constituent that forms the functional core together with Tic20 in the one-megadalton TIC.

Chloroplast Protein Tic55 Involved in Dark-Induced Senescence through AtbHLH/AtWRKY-ANAC003 Controlling Pathway of Arabidopsis thaliana.

The chloroplast comprises the outer and inner membranes that are composed of the translocon protein complexes Toc and Tic (translocon at the outer/inner envelope membrane of chloroplasts), respectively. Tic55, a chloroplast Tic protein member, was shown to be not vital for functional protein import in Arabidopsis from previous studies. Instead, Tic55 was revealed to be a dark-induced senescence-related protein in our earlier study. To explore whether Tic55 elicits other biological functions, a tic55-II knockout mutant (SALK_086048) was characterized under different stress treatments. Abiotic stress conditions, such as cold, heat, and high osmotic pressure, did not cause visible effects on tic55-II mutant plant, when compared to the wild type (WT). In contrast, senescence was induced in the individually darkened leaves (IDLs), resulting in the differential expression of the senescence-related genes PEROXISOME DEFECTIVE 1 (PED1), BLUE COPPER-BINDING PROTEIN (BCB), SENESCENCE 1 (SEN1), and RUBISCO SMALL SUBUNIT GENE 2B (RBCS2B). The absence of Tic55 in tic55-II knockout mutant inhibited expression of the senescence-related genes PED1, BCB, and SEN1 at different stages of dark adaptation, while causing stimulation of RBCS2B gene expression at an early stage of dark response. Finally, yeast one-hybrid assays located the ANAC003 promoter region with cis-acting elements are responsible for binding to the different AtbHLH proteins, thereby causing the transactivation of an HIS3 reporter gene. ANAC003 was shown previously as a senescence-related protein and its activation would lead to expression of senescence-associated genes (SAGs), resulting in plant senescence. Thus, we propose a hypothetical model in which three signaling pathways may be involved in controlling the expression of ANAC003, followed by expression of SAGs that in turn leads to leaf senescence in Arabidopsis by this study and previous data.

Vitamin D levels in children and adolescents with chronic tic disorders: a multicentre study.

This study investigated whether vitamin D is associated with the presence or severity of chronic tic disorders and their psychiatric comorbidities. This cross-sectional study compared serum 25-hydroxyvitamin D [25(OH)D] (ng/ml) levels among three groups: children and adolescents (3-16 years) with CTD (n = 327); first-degree relatives (3-10 years) of individuals with CTD who were assessed for a period of up to 7 years for possible onset of tics and developed tics within this period (n = 31); and first-degree relatives who did not develop tics and were ≥ 10 years old at their last assessment (n = 93). The relationship between 25(OH)D and the presence and severity of tics, as well as comorbid obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD), were analysed controlling for age, sex, season, centre, latitude, family relatedness, and comorbidities. When comparing the CTD cohort to the unaffected cohort, the observed result was contrary to the one expected: a 10 ng/ml increase in 25(OH)D was associated with higher odds of having CTD (OR 2.08, 95% CI 1.27-3.42, p < 0.01). There was no association between 25(OH)D and tic severity. However, a 10 ng/ml increase in 25(OH)D was associated with lower odds of having comorbid ADHD within the CTD cohort (OR 0.55, 95% CI 0.36-0.84, p = 0.01) and was inversely associated with ADHD symptom severity (ß = - 2.52, 95% CI - 4.16-0.88, p < 0.01). In conclusion, lower vitamin D levels were not associated with a higher presence or severity of tics but were associated with the presence and severity of comorbid ADHD in children and adolescents with CTD.

The Roles of Phasic and Tonic Dopamine in Tic Learning and Expression.

Tourette syndrome (TS) prominently involves dopaminergic disturbances, but the precise nature of those disturbances has remained elusive. A substantial body of empirical work and recent computational models have characterized the specific roles of phasic and tonic dopamine (DA) in action learning and selection, respectively. Using insights from this work and models, we suggest that TS involves increases in both phasic and tonic DA, which produce increased propensities for tic learning and expression, respectively. We review the evidence from reinforcement-learning and habit-learning studies in TS, which supports the idea that TS involves increased phasic DA responses; we also review the evidence that tics engage the habit-learning circuitry. On the basis of these findings, we suggest that tics are exaggerated, maladaptive, and persistent motor habits reinforced by aberrant, increased phasic DA responses. Increased tonic DA amplifies the tendency to execute learned tics and also provides a fertile ground of motor hyperactivity for tic learning. We review evidence suggesting that antipsychotics may counter both the increased propensity for tic expression, by increasing excitability in the indirect pathway, and the increased propensity for tic learning, by shifting plasticity in the indirect pathway toward long-term potentiation (and possibly also through more complex mechanisms). Finally, we review evidence suggesting that low doses of DA agonists that effectively treat TS decrease both phasic and tonic DA, thereby also reducing the propensity for both tic learning and tic expression, respectively.

Gilles de la Tourette syndrome is associated with hypermethylation of the dopamine D2 receptor gene.

Several lines of evidence support a "dopaminergic hypothesis" in the pathophysiology of Gilles de la Tourette syndrome (TS). The aim of this study was to investigate for the first time epigenetic changes in DNA methylation in different dopamine genes in adult patients with TS. We included 51 well characterized adult patients with TS (41 males, 10 females, mean age = 35 ± 12.6 years, range, 18-71 years) and compared results with data from a group of 51 sex- and age-matched healthy controls. Bisulfite sequencing was used to measure peripheral DNA methylation of the dopamine transporter (DAT), the dopamine D2 receptor (DRD2), and the catechol-O-methyltransferase (COMT) genes. Compared to healthy controls, patients with TS showed significantly elevated methylation level of the DRD2 gene that positively correlated with tic severity. In contrast, DAT methylation was lower in more severely affected patients. Our results provide evidence for a role of altered epigenetic regulation of dopaminergic genes in the pathophysiology of TS. While DRD2 hypermethylation seems to be directly related to the neurobiology of TS that may lead to dopaminergic dysfunction resulting in enhanced thalamo-cortical movement-stimulating activity, DAT hypomethylation might reflect a secondary mechanism in order to compensate for increased dopaminergic signal transduction due to DRD2 hypermethylation. In addition, it can be speculated that spontaneous fluctuations of tics may be caused by short-term alterations of methylation levels of dopaminergic genes resulting in dynamic changes of tonic/phasic dopaminergic signaling in the striatum and thalamo-cortical output pathways.

Dopamine depleters in the treatment of hyperkinetic movement disorders.

INTRODUCTION: Abnormal involuntary movements often improve in response to anti-dopaminergic drugs. In contrast to classic neuroleptics that block dopamine receptors, drugs that deplete presynaptic dopamine by blocking vesicular monoamine transporter type 2 (VMAT2) seem to be safer and have little or no risk of tardive dyskinesia. This is one reason why there has been a recent emergence of novel VMAT2 inhibitors. Areas covered: Since the approval of tetrabenazine, the classic VMAT2 inhibitor, in the treatment of chorea associated with Huntington disease (HD), other VMAT2 inhibitors (e.g. deutetrabenazine and valbenazine) have been studied in the treatment of HD-related chorea, tardive dyskinesia and tics associated with Tourette syndrome. This review, based largely on a detailed search of PubMed, will summarize the pharmacology and clinical experience with the various VMAT2 inhibitors. Expert commentary: Because of differences in pharmacology and pharmacokinetics these new VMAT2 inhibitors promise to be at least as effective as tetrabenazine but with a lower risk of adverse effects, such as sedation, insomnia, depression, parkinsonism, and akathisia.

"Hyperglutamatergic cortico-striato-thalamo-cortical circuit" breaker drugs alleviate tics in a transgenic circuit model of Tourette׳s syndrome.

The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies.

Lingual dyskinesia and tics: a novel presentation of copper-metabolism disorder.

Copper is a trace element that is required for cellular respiration, neurotransmitter biosynthesis, pigment formation, antioxidant defense, peptide amidation, and formation of connective tissue. Abnormalities of copper metabolism have been linked with neurologic disorders that affect movement, such as Wilson disease and Menkes disease; however, the diagnosis of non-Wilson, non-Menkes-type copper-metabolism disorders has been more elusive, especially in cases with atypical characteristics. We present here the case of an adolescent with a novel presentation of copper-metabolism disorder who exhibited acute severe hemilingual dyskinesia and prominent tics, with ballismus of the upper limbs, but had normal brain and spinal MRI results and did not show any signs of dysarthria or dysphagia. His serum copper and ceruloplasmin levels were low, but his urinary copper level was elevated after penicillamine challenge. We conclude that copper-metabolism disorders should be included in the differential diagnosis for movement disorders, even in cases with highly unusual presentations, because many of them are treatable. Moreover, a connection between copper-metabolism disorders and tics is presented, to our knowledge, for the first time in humans; further investigation is needed to better establish this connection and understand its underlying pathophysiology.

[Tourette syndrome. Genetics, neuroanatomy and neurotransmitters]. / Tourettes syndrom. Genetik, neuroanatomi og neurotransmittere.

The etiology and pathophysiology of Tourette syndrome (TS) have not yet been clarified. Despite inconsistencies in the literature, some conclusions can be drawn on genetics, neuroanatomy and neurotransmitters. The inheritance of TS is unknown; the etiology seems to be polygenic. The basal ganglia are probably smaller in patients with TS. A dysfunction in the dopaminergic pathway causes tics. ADHD results from a decreased concentration of dopamine and an increased concentration of noradrenaline. OCD is caused by a dysfunction in serotonin and probably dopamine.

Identification of pyruvate kinase as an antigen associated with Tourette syndrome.

Immune responses to beta-hemolytic streptococcal infections are hypothesized to trigger tic disorders and early-onset obsessive-compulsive disorder (OCD) in some pediatric populations. Here we identify the M1 isoform of the glycolytic enzyme, pyruvate kinase (PK) as an autoimmune target in Tourette syndrome and associated disorders. Antibodies to PK reacted strongly with surface antigens of infectious strains of streptococcus, and antibodies to streptococcal M proteins reacted with PK. Moreover, immunoreactivity to PK in patients with exacerbated symptoms who had recently acquired a streptococcal infection was 7-fold higher compared to patients with exacerbated symptoms and no evidence of a streptococcal infection. These data suggest that PK can function as an autoimmune target and that this immunoreactivity may be associated with Tourette syndrome, OCD, and associated disorders.

Phenomenology of tics and natural history of tic disorders.

Tic symptoms, the hallmark of Tourette's syndrome (TS), may simply be fragments of innate behavior. As such, the sensory urges that precede tics may illuminate some of the normal internal cues that are intimately involved in the assembly of behavioral sequences. The occurrence of tics in time appears to have fractal characteristics that may help to explain the waxing and waning course of tic disorders. Longitudinal studies are currently underway that should permit a close examination of the natural fluctuations in tic severity using valid and reliable clinician-rated scales of tic severity. The natural history of tics typically shows a marked decline during the course of adolescence. However, TS can also be associated with social, emotional, and academic difficulties in early adulthood. Comorbid attention deficit/hyperactivity disorder and obsessive-compulsive disorder are likely to influence the long-term adaptive outcomes of individuals with TS. Future progress may also be expected as endophenotypes, and possibly genetic markers, are identified that are associated with specific comorbid conditions and etiologically distinct forms of TS.

The role of positron emission tomography imaging in movement disorders.

PET imaging provides the means to study neurochemical, hemodynamic, or metabolic processes that underlie movement disorders in vivo. Because the extent of presynaptic nigrostriatal dopaminergic denervation can be quantified in PD even at an early or preclinical stage of the disease, PET imaging may allow the selection of at-risk subjects for neuroprotective intervention trials. These techniques may also provide markers to follow progression of disease or evaluate the effects of neurorestorative interventions in patients who have more advanced disease. PET is expected to play an increasing role in the selection of patients who have PD for deep brain stimulation. Dopaminergic studies may have a limited clinical role in the diagnosis of patients who have symptoms that suggestive of PD yet do not respond to typical dopaminergic drugs, such as patients who have vascular parkinsonism or ET with mild resting tremor who may have normal dopaminergic innervation. The differential diagnosis between PD and multiple system atrophy, progressive supranuclear palsy, or corticobasal degeneration is not yet clearly established by PET, but combined pre- and postsynaptic dopaminergic imaging may be able to distinguish early idiopathic PD from atypical parkinsonian disorders, in general. Huntington's chorea is characterized by more prominent striatal dopamine receptor loss, whereas nigrostriatal denervation is present to a lesser degree. Patients who have TS may have enhanced synaptic dopamine release in the putamen. Functional imaging studies have generally failed to demonstrate nigrostriatal denervation in essential tremor or idiopathic dystonia. Studies have shown striatal dopamine receptor loss in selected subtypes of dystonic patients. In conclusion, it is expected that PET will help us to better understand the pathophysiology of movement disorders, increase the diagnostic accuracy, allow preclinical diagnosis, monitor disease progression, and evaluate the efficacy of therapeutic agents. Pharmacologic radioligand displacement studies and the development of new nondopaminergic ligands may further aid in the unraveling of cerebral mechanisms that underlie movement disorders.