A novel GTPCH deficiency mouse model exhibiting tetrahydrobiopterin-related metabolic disturbance and infancy-onset motor impairments

Jiang, Xiaoling; Liu, Huazhen; Shao, Youxiang; Peng, Mingzhi; Zhang, Wen; Li, Duan; Li, Xiuzhen; Cai, Yamei; Ting, Tan Chen; Lu, Xinshuo; Xu, Jianan; Su, Xueying; Lin, Yunting; Liu, Zongcai; Huang, Yi‐Zhi; Zeng, Chunhua; Tang, Yaping; Liu, Li

doi:10.1016/j.metabol.2019.02.001

Cited by 13 publications

(8 citation statements)

References 31 publications

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“…These animal models demonstrate that BH 4 regulates catecholamine synthesis through altering TH protein levels and that the postnatally expected increase of dopamine and TH protein concentration in the brain is disrupted by BH 4 deficiency 23 , 25 . Maternal compensation of BH 4 and dopamine deficiency as well as postnatal rescue has been demonstrated to be possible but limited 20 – 22 , 24 , 25 , 30 . Further studies will be needed to elucidate the disease-related pre- and postnatal findings of our study and the effectiveness and limitations of maternal metabolic compensation.…”

Section: Discussionmentioning

confidence: 99%

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines

et al. 2021

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Inherited disorders of neurotransmitter metabolism are rare neurodevelopmental diseases presenting with movement disorders and global developmental delay. This study presents the results of the first standardized deep phenotyping approach and describes the clinical and biochemical presentation at disease onset as well as diagnostic approaches of 275 patients from the registry of the International Working Group on Neurotransmitter related Disorders. The results reveal an increased rate of prematurity, a high risk for being small for gestational age and for congenital microcephaly in some disorders. Age at diagnosis and the diagnostic delay are influenced by the diagnostic methods applied and by disease-specific symptoms. The timepoint of investigation was also a significant factor: delay to diagnosis has decreased in recent years, possibly due to novel diagnostic approaches or raised awareness. Although each disorder has a specific biochemical pattern, we observed confounding exceptions to the rule. The data provide comprehensive insights into the phenotypic spectrum of neurotransmitter disorders.

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Section: Discussionmentioning

confidence: 99%

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines

et al. 2021

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“…Moreover, interactions within different components of the NT synthesis pathway can be altered in disease state, with the exact mechanisms and long‐term implications not fully understood. One example is different BH 4 deficiency murine models, namely sepiapterin reductase, 150 PTPS, 151 and GCH1, 152 where reduction in TH protein levels, particularly in striatum, were observed, impacting foetal DA circuit development 153 . Normal TH levels, therefore, appear critical for psychomotor function and DA system maturation 154 .…”

Section: Discussionmentioning

confidence: 99%

Gene therapy for neurotransmitter‐related disorders

Chu,

Ng,

Waddington

et al. 2024

J of Inher Metab Disea

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Inborn errors of neurotransmitter (NT) metabolism are a group of rare, heterogenous diseases with predominant neurological features, such as movement disorders, autonomic dysfunction, and developmental delay. Clinical overlap with other disorders has led to delayed diagnosis and treatment, and some conditions are refractory to oral pharmacotherapies. Gene therapies have been developed and translated to clinics for paediatric inborn errors of metabolism, with 38 interventional clinical trials ongoing to date. Furthermore, efforts in restoring dopamine synthesis and neurotransmission through viral gene therapy have been developed for Parkinson's disease. Along with the recent European Medicines Agency (EMA) and Medicines and Healthcare Products Regulatory Agency (MHRA) approval of an AAV2 gene supplementation therapy for AADC deficiency, promising efficacy and safety profiles can be achieved in this group of diseases. In this review, we present preclinical and clinical advances to address NT‐related diseases, and summarise potential challenges that require careful considerations for NT gene therapy studies.

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“…Only recent genome-wide association studies with genetic information from a large number of HD patients predicted that DHFR is possibly a modifier of disease progression [ 5 , 56 ]. In addition, genetic defects in DHFR were found to cause insufficient cerebral BH 4 levels [ 40 ], while GTPCH-deficient mice exhibited BH 4 -related metabolic disturbance and infancy-onset motor impairments [ 57 ]. These previous reports point to the importance of maintaining normal expression of GTPCH and DHFR in animals.…”

Section: Discussionmentioning

confidence: 99%

A plant-based mutant huntingtin model-driven discovery of impaired expression of GTPCH and DHFR

Hung

Zhu

Kittur

et al. 2022

Cell. Mol. Life Sci.

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Pathophysiology associated with Huntington’s disease (HD) has been studied extensively in various cell and animal models since the 1993 discovery of the mutant huntingtin (mHtt) with abnormally expanded polyglutamine (polyQ) tracts as the causative factor. However, the sequence of early pathophysiological events leading to HD still remains elusive. To gain new insights into the early polyQ-induced pathogenic events, we expressed Htt exon1 (Httex1) with a normal (21), or an extended (42 or 63) number of polyQ in tobacco plants. Here, we show that transgenic plants accumulated Httex1 proteins with corresponding polyQ tracts, and mHttex1 induced protein aggregation and affected plant growth, especially root and root hair development, in a polyQ length-dependent manner. Quantitative proteomic analysis of young roots from severely affected Httex1Q63 and unaffected Httex1Q21 plants showed that the most reduced protein by polyQ63 is a GTP cyclohydrolase I (GTPCH) along with many of its related one-carbon (C1) metabolic pathway enzymes. GTPCH is a key enzyme involved in folate biosynthesis in plants and tetrahydrobiopterin (BH4) biosynthesis in mammals. Validating studies in 4-week-old R6/2 HD mice expressing a mHttex1 showed reduced levels of GTPCH and dihydrofolate reductase (DHFR, a key folate utilization/alternate BH4 biosynthesis enzyme), and impaired C1 and BH4 metabolism. Our findings from mHttex1 plants and mice reveal impaired expressions of GTPCH and DHFR and may contribute to a better understanding of mHtt-altered C1 and BH4 metabolism, and their roles in the pathogenesis of HD.

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A novel GTPCH deficiency mouse model exhibiting tetrahydrobiopterin-related metabolic disturbance and infancy-onset motor impairments

Cited by 13 publications

References 31 publications

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines

Insights into the expanding phenotypic spectrum of inherited disorders of biogenic amines

Gene therapy for neurotransmitter‐related disorders

A plant-based mutant huntingtin model-driven discovery of impaired expression of GTPCH and DHFR

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