Dopa‐responsive dystonia: Pathological and biochemical observations in a case

Rajput, Alex; Gibb, W. R. G.; Zhong, Xiaohui H.; Shannak, Kathleen; Kish, Stephen J.; Chang, Lijia; Hornykiewicz, Oleh

doi:10.1002/ana.410350405

Cited by 181 publications

(102 citation statements)

References 16 publications

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“…Our experiments further demonstrate that a loss of TH protein in the terminal regions of the nigrostriatal tract is a principal pathology of the basal ganglia in the DPS mice, as has been found in human DRD patients (9,20,21). These observations validate the DPS mouse as a model of DRD.…”

Section: Discussionsupporting

confidence: 62%

“…S1] (5)(6)(7)(8). Loss of dopamine in the striatum, together with reduced striatal TH activity and TH protein, are the key features that have been observed in the rare autopsied cases of autosomal dominant DRD (9). Some parkinsonian symptoms are present in DRD, especially with increasing age, but dystonia is predominant.…”

Section: Dopa-responsive Dystonia (Drd) Is a Hereditary Dystonia Charmentioning

confidence: 99%

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Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia

Sato

Sumi‐Ichinose

Kaji

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Dopa-responsive dystonia (DRD) is a hereditary dystonia character-ized by a childhood onset of fixed dystonic posture with a dramatic and sustained response to relatively low doses of levodopa. DRD is thought to result from striatal dopamine deficiency due to a reduced synthesis and activity of tyrosine hydroxylase (TH), the synthetic enzyme for dopamine. The mechanisms underlying the genesis of dystonia in DRD present a challenge to models of basal ganglia movement control, given that striatal dopamine deficiency is the hallmark of Parkinson's disease. We report here behavioral and anatomical observations on a transgenic mouse model for DRD in which the gene for 6-pyruvoyl-tetrahydropterin synthase is targeted to render selective dysfunction of TH synthesis in the striatum. Mutant mice exhibited motor deficits phenotypically resembling symptoms of human DRD and manifested a major depletion of TH labeling in the striatum, with a marked posterior-to-anterior gradient resulting in near total loss caudally. Strikingly, within the regions of remaining TH staining in the striatum, there was a greater loss of TH labeling in striosomes than in the surrounding matrix. The predominant loss of TH expression in striosomes occurred during the early postnatal period, when motor symptoms first appeared. We suggest that the differential striosome-matrix pattern of dopamine loss could be a key to identifying the mechanisms underlying the genesis of dystonia in DRD.basal ganglia ͉ movement disorders ͉ Parkinson's disease ͉ striatum

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Section: Discussionsupporting

confidence: 62%

Section: Dopa-responsive Dystonia (Drd) Is a Hereditary Dystonia Charmentioning

confidence: 99%

Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia

Sato

Sumi‐Ichinose

Kaji

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Some patients with SPR deficiency show similar age-dependent alterations in clinical symptoms (11). These symptoms are well responsive to the L-DOPA treatment and thought to be caused by dysfunction of the nigrostriatal dopaminergic system due to insufficient production of dopamine in the striatum (12,13). However, it is poorly understood why dystonia appears in childhood but not in the neonatal period.…”

Section: Tetrahydrobiopterin (Bh4)mentioning

confidence: 99%

Partial Biopterin Deficiency Disturbs Postnatal Development of the Dopaminergic System in the Brain

Homma

Sumi‐Ichinose

Tokuoka

et al. 2011

Journal of Biological Chemistry

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Postnatal development of dopaminergic system is closely related to the development of psychomotor function. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the biosynthesis of dopamine and requires tetrahydrobiopterin (BH4) as a cofactor. To clarify the effect of partial BH4 deficiency on postnatal development of the dopaminergic system, we examined two lines of mutant mice lacking a BH4-biosynthesizing enzyme, including sepiapterin reductase knock-out (Spr ؊/؊ ) mice and genetically rescued 6-pyruvoyltetrahydropterin synthase knock-out (DPS-Pts ؊/؊ ) mice. We found that biopterin contents in the brains of these knock-out mice were moderately decreased from postnatal day 0 (P0) and remained constant up to P21. In contrast, the effects of BH4 deficiency on dopamine and TH protein levels were more manifested during the postnatal development. Both of dopamine and TH protein levels were greatly increased from P0 to P21 in wild-type mice but not in those mutant mice. Serotonin levels in those mutant mice were also severely suppressed after P7. Moreover, striatal TH immunoreactivity in Spr ؊/؊ mice showed a drop in the late

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“…DRD is caused by disturbed BH4 synthesis (15). Autopsied brains of patients with the disease showed a marked reduction in the content of TH protein in the striatum (48,49).…”

Section: -Pyruvoyltetrahydropterin Synthase Knockout Micementioning

confidence: 99%

Catecholamines and Serotonin Are Differently Regulated by Tetrahydrobiopterin

Sumi‐Ichinose¹,

Urano²,

Kuroda³

et al. 2001

Journal of Biological Chemistry

126

100

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(6R)-L-erythro-5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for tyrosine hydroxylase (TH), tryptophan hydroxylase, phenylalanine hydroxylase, and nitric-oxide synthase. These enzymes synthesize neurotransmitters, e.g. catecholamines, serotonin, and nitric oxide (NO). We established mice unable to synthesize BH4 by disruption of the 6-pyruvoyltetrahydropterin synthase gene, the encoded protein of which catalyzes the second step of BH4 biosynthesis. Homozygous mice were born at the almost expected Mendelian ratio, but died within 48 h after birth. In the brain of homozygous mutant neonates, levels of biopterin, catecholamines, and serotonin were extremely low. The number of TH molecules was highly dependent on the intracellular concentration of BH4 at nerve terminals. Alteration of the TH protein level by modulation of the BH4 content is a novel regulatory mechanism. Our data showing that catecholaminergic, serotonergic, and NO systems were differently affected by BH4 starvation suggest the possible involvement of BH4 synthesis in the etiology of monoamine-based neurological and neuropsychiatric disorders.Catecholamines, e.g. dopamine (DA), 1 norepinephrine (NE), and epinephrine, and serotonin (5-hydroxytryptamine; 5HT) are well known to be involved in many aspects of brain function, including mood, addiction, reward, and sleep. Alteration in the metabolism of these monoamines leads to abnormalities in behavior and neuropsychiatric states. For example, increased dopaminergic neurotransmission in the mesolimbic system induces hallucinations, illusions, and delusions, which are the major symptoms of schizophrenia (1). Depletion of monoamines may be the cause of depression, because drugs that can increase the level of monoamines and blockers of norepinephrine or serotonin uptake show therapeutic effects in patients with depression (2). Abnormal monoamine metabolism is also suspected to be involved in Tourette's syndrome, obsessive-compulsive disorder, Rett syndrome, and infantile autism (3, 4).Biosynthesis of catecholamines and serotonin is mainly regulated by the activity of the hydroxylation reaction catalyzed by tyrosine hydroxylase (TH) in catecholamine synthesis (5) and by tryptophan hydroxylase (TPH) in 5HT synthesis (6). The TH activity is tightly regulated by several factors (for review, see Ref. 7 and references therein). Short term regulation is achieved by phosphorylation of the enzyme and by feedback inhibition with the end products. Long term regulation is mainly governed at the transcriptional level.(6R)-L-erythro-5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for both TH and TPH. Although many cofactors such as folic acid and cobalamin (vitamin B12) are required to be dietary supplemented, mammals have a de novo biosynthetic pathway for BH4. In this pathway, guanosine triphosphate (GTP) is converted to 7,8-dihydroneopterin triphosphate by GTP cyclohydrolase 1 (GCH), and 7,8-dihydroneopterin triphosphate is then converted to 6-pyruvoyltetrahydropterin by pyruvoyltetrahydropteri...

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Dopa‐responsive dystonia: Pathological and biochemical observations in a case

Cited by 181 publications

References 16 publications

Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia

Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia

Partial Biopterin Deficiency Disturbs Postnatal Development of the Dopaminergic System in the Brain

Catecholamines and Serotonin Are Differently Regulated by Tetrahydrobiopterin

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