α-Synuclein and mitochondrial bioenergetics regulate tetrahydrobiopterin levels in a human dopaminergic model of Parkinson disease

Ryan, Brent J.; Lourenço-Venda, Lara L.; Crabtree, Mark J.; Hale, Ashley; Channon, Keith M.; Wade‐Martins, Richard

doi:10.1016/j.freeradbiomed.2013.10.008

Cited by 27 publications

(27 citation statements)

References 41 publications

(48 reference statements)

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“…We found that iron caused a chronic depletion of striatal DA and BH4 levels, which was preceded by initial increase in striatal DA and BH4 concentration. In line with our findings, BH4 levels are decreased at 24 h in MPP + (1-methyl-4-phenylpyridinium)-induced human dopaminergic model of PD [33]. Previous our findings show that MPTP induce the reduction of DA but not BH4 level in striatum and SN [34].…”

Section: Discussionsupporting

confidence: 93%

Alteration of striatal tetrahydrobiopterin in iron-induced unilateral model of Parkinson's disease

Aryal

2016

Parkinsonism & Related Disorders

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It has been suggested that transition metal ions such as iron can produce an oxidative injuries to nigrostriatal dopaminergic neurons, like Parkinson's disease (PD) and subsequent compensative increase of tetrahydrobiopterin (BH4) during the disease progression induces the aggravation of dopaminergic neurodegeneration in striatum. It had been established that the direct administration of BH4 into neuron would induce the neuronal toxicity in vitro. To elucidate a role of BH4 in pathogenesis in the PD in vivo, we assessed the changes of dopamine (DA) and BH4 at striatum in unilateral intranigral iron infused PD rat model. The ipsistriatal DA and BH4 levels were significantly increased at 0.5 to 1 d and were continually depleting during 2 to 7 d after intranigral iron infusion. The turnover rate of BH4 was higher than that of DA in early phase. However, the expression level of GTPcyclohydrolase I mRNA in striatum was steadily increased after iron administration. These results suggest that the accumulation of intranigral iron leads to generation of oxidative stress which damage to dopaminergic neurons and causes increased release of BH4 in the dopaminergic neuron. The degenerating dopaminergic neurons decrease the synthesis and release of both BH4 and DA in vivo that are relevance to the progression of PD. Based on these data, we propose that the increase of BH4 can deteriorate the disease progression in early phase of PD, and the inhibition of BH4 increase could be a strategy for PD treatment.

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Section: Discussionsupporting

confidence: 93%

Alteration of striatal tetrahydrobiopterin in iron-induced unilateral model of Parkinson's disease

Aryal

2016

Parkinsonism & Related Disorders

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“…l -DOPA levels were quantified as previously described (Ryan et al, 2014). Briefly, samples were injected onto an isocratic HPLC system and quantified using a Decade SDC detector and a carbon working electrode held at +0.7 V vs a Ag/AgCl reference electrode (Antec).…”

Section: Methodsmentioning

confidence: 99%

A requirement for Gch1 and tetrahydrobiopterin in embryonic development

Douglas

Hale

Crabtree

et al. 2015

Developmental Biology

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IntroductionGTP cyclohydrolase I (GTPCH) catalyses the first and rate-limiting reaction in the synthesis of the enzymatic cofactor, tetrahydrobiopterin (BH4). Loss of function mutations in the GCH1 gene lead to congenital neurological diseases such as DOPA-responsive dystonia and hyperphenylalaninemia. However, little is known about how GTPCH and BH4 affects embryonic development in utero, and in particular whether metabolic replacement or supplementation in pregnancy is sufficient to rescue genetic GTPCH deficiency in the developing embryo.Methods and resultsGch1 deficient mice were generated by the insertion of loxP sites flanking exons 2–3 of the Gch1 gene. Gch1fl/fl mice were bred with Sox2cre mice to generate mice with global Gch1 deficiency. Genetic ablation of Gch1 caused embryonic lethality by E13.5. Despite loss of Gch1 mRNA and GTPCH enzymatic activity, whole embryo BH4 levels were maintained until E11.5, indicating sufficient maternal transfer of BH4 to reach this stage of development. After E11.5, Gch1−/− embryos were deficient in BH4, but an unbiased metabolomic screen indicated that the lethality was not due to a gross disturbance in metabolic profile. Embryonic lethality in Gch1−/− embryos was not caused by structural abnormalities, but was associated with significant bradycardia at E11.5. Embryonic lethality was not rescued by maternal supplementation of BH4, but was partially rescued, up to E15.5, by maternal supplementation of BH4 and l-DOPA.ConclusionThese findings demonstrate a requirement for Gch1 in embryonic development and have important implications for the understanding of pathogenesis and treatment of genetic BH4 deficiencies, as well as the identification of new potential roles for BH4.

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“…In the mitochondrial realm, diseased cells show changes in metabolic pathways[1,2], respiration rates [3,4], reactive oxygen species generation [3,5], and even mitochondrial morphology [6,7] or motility [8,9]. On the other hand, damaged cytoarchitecture can manifest as changes in cell shape [10], traction force generation [11], or stiffness of the extracellular matrix [12,13] or the cell itself [14,15].…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial respiration is sensitive to cytoarchitectural breakdown

Kandel

Angelin

Wallace

et al. 2016

Integrative Biology

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An abundance of research suggests that cellular mitochondrial and cytoskeletal disruption are related, but few studies have directly investigated causative connections between the two. We previously demonstrated that inhibiting microtubule and microfilament polymerization affects mitochondrial motility on the whole-cell level in fibroblasts. Since mitochondrial motility can be indicative of mitochondrial function, we now further characterize the effects of these cytoskeletal inhibitors on mitochondrial potential, morphology and respiration. We found that although they did not reduce mitochondrial inner membrane potential, cytoskeletal toxins induced significant decreases in basal mitochondrial respiration. In some cases, basal respiration was only affected after cells were pretreated with the calcium ionophore A23187 in order to stress mitochondrial function. In most cases, mitochondrial morphology remained unaffected, but extreme microfilament depolymerization or combined intermediate doses of microtubule and microfilament toxins resulted in decreased mitochondrial lengths. Interestingly, these two particular exposures did not affect mitochondrial respiration in cells not sensitized with A23187, indicating an interplay between mitochondrial morphology and respiration. In all cases, inducing maximal respiration diminished differences between control and experimental groups, suggesting that reduced basal respiration originates as a largely elective rather than pathological symptom of cytoskeletal impairment. However, viability experiments suggest that even this type of respiration decrease may be associated with cell death.

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α-Synuclein and mitochondrial bioenergetics regulate tetrahydrobiopterin levels in a human dopaminergic model of Parkinson disease

Cited by 27 publications

References 41 publications

Alteration of striatal tetrahydrobiopterin in iron-induced unilateral model of Parkinson's disease

Alteration of striatal tetrahydrobiopterin in iron-induced unilateral model of Parkinson's disease

A requirement for Gch1 and tetrahydrobiopterin in embryonic development

Mitochondrial respiration is sensitive to cytoarchitectural breakdown

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