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The autosomal recessive defect of aromatic L‐amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2‐based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally‐delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow‐up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality‐assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long‐term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow‐up plan and systematic documentation of outcomes in a suitable, industry‐independent registry study are necessary. [ABSTRACT FROM AUTHOR]

Abstract Aromatic l‐amino acid decarboxylase (AADC) deficiency is a rare inherited disorder that affects neurotransmitter biosynthesis. A DDC founder mutation c.714 + 4A > T (IVS6 + 4A > T) is prevalent in the Chinese population. This study investigated the epidemiology of AADC deficiency in Taiwan by analyzing data from National Taiwan University Hospital (NTUH), a central institution for diagnosing and treating the disease. From January 2000 to March 2023, 77 patients with AADC deficiency visited NTUH. Among them, eight were international patients seeking a second opinion, and another two had one or both non‐Chinese parents; all others were ethnically Chinese. The c.714 + 4A > T mutation accounted for 85% of all mutated alleles, and 94% of patients exhibited a severe phenotype. Of the 77 patients, 31 received gene therapy at a mean age of 3.76 years (1.62–8.49) through clinical trials, and their current ages were significantly older than those of the remaining patients. Although the combined incidence of AADC deficiency in this study (1:66491 for 2004 and later) was lower than that reported in newborn screening (1:31997 to 1:42662), case surges coincided with the launch of clinical trials and the implementation of newborn screening. Currently, many young patients are awaiting for treatment.

The mammalian striatum is known to contain non-dopaminergic neurons that express dopamine (DA)-synthesizing enzymes and produce DA, responsible for the regulation of motor function. This study assessed the expression of DA-synthesizing enzymes in striatal neurons and their role in DA synthesis in transgenic mice expressing the green fluorescent protein (GFP) gene under the tyrosine hydroxylase (TH) gene promoter in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease (PD). We showed that, in Parkinsonian animals, the number of neurons expressing the TH gene increased by 1.9 times compared with the control (0.9% NaCl), which indicates a compensatory response to the DAergic denervation of the striatum. This assumption is supported by a 2.5-fold increase in the expression of genes for TH and transcription factor Nurr1 and a 1.45-fold increase in the expression of the large amino acid transporter 1 gene. It is noteworthy that, in Parkinsonian mice, in contrast to the controls, DA-synthesizing enzymes were found not only in nerve fibers but also in neuronal cell bodies. Indeed, TH or TH and aromatic L-amino acid decarboxylase (AADC) were detected in GFP-positive neurons, and AADC was detected in GFP-negative neurons. These neurons were shown to synthesize DA, and this synthesis is compensatorily increased in Parkinsonian mice. The above data open the prospect of improving the treatment of PD by maintaining DA homeostasis in the striatum. [ABSTRACT FROM AUTHOR]

Keywords: Dopamine; Tyrosine hydroxylase; Neuromelanin; Neuroprotection; Neurodegeneration; Neurotoxicity; DT-diaphorase; Glutathione transferase M2-2; VMAT-2; Aromatic l-amino acid decarboxylase EN Dopamine Tyrosine hydroxylase Neuromelanin Neuroprotection Neurodegeneration Neurotoxicity DT-diaphorase Glutathione transferase M2-2 VMAT-2 Aromatic l-amino acid decarboxylase 1 4 4 09/12/23 20231001 NES 231001 Commentary on: DOI: https://doi.org/10.1007/s00018-022-04574-x. However, the synthesis of neuromelanin requires the formation of three potentially neurotoxic ortho-quinones in a sequential manner (dopamine - > dopamine ortho-quinone - > aminochrome - > 5,6-indolequinone - > neuromelanin). Dopamine synthesis is catalyzed by TH which catalyzes the introduction of a hydroxyl group into the amino acid tyrosine which converts it to l-dopa, which is converted to dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC). [Extracted from the article]

Aromatic L‑amino acid decarboxylase (AADC) deficiency is rare autosomal recessive neurometabolic disorder. It caused by generalized combined deficiency of serotonin, dopamine, norepinephrine and adrenaline. This disorder is characterized by muscular hypotonia, motor development delay, oculogyric crises and impairment of the autonomic nervous system.Laboratory diagnostic of AADC deficiency in Russian Federation includes determination of the concentration of 3‑O‑methyldophamine in dried blood spots by tandem mass spectrometry and molecular analysis of the DDC gene by Sanger sequencing or next generation sequencing.Therapy of AADC deficiency includes combination of drugs which increase the formation of dopamine, inhibit its reuptake and increase the residual activity of the enzyme. The first‑line drugs are selective dopamine agonists, monoamine oxidase inhibitors of type B and vitamin B6 supplements.We present the case of management and treatment of patients with AADC deficiency. The patient’s condition was improved by using of combination therapy with pyridoxal‑5‑phosphate, pramipexole and selegiline. Significant positive dynamics was achieved on pyridoxal‑5‑phosphate therapy for the first time.

We have recently shown that the periventricular nucleus (PeVN) of adult rats is a "mixed dopaminergic (DAergic) center" containing three thousand neurons: DAergic neurons and those expressing one of the dopamine (DA)-synthesizing enzymes. This study aims to evaluate the development of the PeVN as a mixed DAergic center in rats in the perinatal period, critical for brain morphogenesis. During this period, the PeVN contains DAergic neurons and monoenzymatic neurons expressing individual enzymes of DA synthesis: tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). In the perinatal period, the total number of such neurons triples, mainly due to monoenzymatic neurons; the content of L-DOPA, the end product of monoenzymatic TH neurons, doubles; and the content of DA, the end product of monoenzymatic AADC neurons and DAergic neurons, increases sixfold. Confocal microscopy has shown that, in the PeVN, all types of neurons and their processes are in close relationships, which suggests their mutual regulation by L-DOPA and DA. In addition, monoenzymatic and DAergic fibers are close to the third cerebral ventricle, located in the subependymal zone, between ependymal cells and in the supraependymal zone. These observations suggest that these fibers deliver L-DOPA and DA to the cerebrospinal fluid, participating in the neuroendocrine regulation of the brain. [ABSTRACT FROM AUTHOR]

• Hypothalamic dopaminergic neurons contain dopamine-synthesizing enzymes a dopamine transporter. • Some hypothalamic neurons contain individual or both enzymes of dopamine synthesis but lack the dopamine transporter. • Hypothalamic neurons with both dopamine-synthesizing enzymes secrete it as a neurotransmitter. • Neurons expressing only tyrosine hydroxylase secrete L-DOPA as a neurotransmitter or a precursor for the cooperative synthesis of dopamine in neurons containing aromatic L-amino acid decarboxylase. • Neurons containing only the dopamine transporter appear to serve to maintain dopamine homeostasis. The hypothalamus is a key link in neuroendocrine regulations, which are provided by neuropeptides and dopamine. Until the late 1980 s, it was believed that, along with peptidergic neurons, hypothalamus contained dopaminergic neurons. Over time, it has been shown that besides dopaminergic neurons expressing the dopamine transporter and dopamine-synthesizing enzymes − tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) − the hypothalamus contains neurons expressing only TH, only AADC, both enzymes or only dopamine transporter. The end secretory product of TH neurons is L-3,4-dihydroxyphenylalanine, while that of AADC neurons and bienzymatic neurons lacking the dopamine transporter is dopamine. During ontogenesis, especially in the perinatal period, monoenzymatic neurons predominate in the hypothalamic neuroendocrine centers. It is assumed that L-3,4-dihydroxyphenylalanine and dopamine are released into the neuropil, cerebral ventricles, and blood vessels, participating in the regulation of target cell differentiation in the perinatal period and the functioning of target cells in adulthood. [ABSTRACT FROM AUTHOR]

Since the discovery of striatal neurons expressing dopamine-synthesizing enzymes, researchers have attempted to identify their phenotype and functional significance. In this study, it was shown that in transgenic mice expressing green fluorescent protein (GFP) under the tyrosine hydroxylase (TH) gene promoter, (i) there are striatal neurons expressing only TH, only aromatic L-amino acid decarboxylase (AADC), or both enzymes of dopamine synthesis; (ii) striatal neurons expressing dopamine-synthesizing enzymes are not dopaminergic since they lack a dopamine transporter; (iii) monoenzymatic neurons expressing individual complementary dopamine-synthesizing enzymes produce this neurotransmitter in cooperation; (iv) striatal nerve fibers containing only TH, only AADC, or both enzymes project into the lateral ventricles, providing delivery pathways for L-3,4-dihydroxyphenylalanine and dopamine to the cerebrospinal fluid; and (v) striatal GFP neurons express receptor genes for various signaling molecules, i.e., classical neurotransmitters, neuropeptides, and steroids, indicating fine regulation of these neurons. Based on our data, it is assumed that the synthesis of dopamine by striatal neurons is a compensatory response to the death of nigral dopaminergic neurons in Parkinson's disease, which opens broad prospects for the development of a fundamentally novel antiparkinsonian therapy. [ABSTRACT FROM AUTHOR]

Since the 1980s, the concept of dopamine-rich brain centers as clusters of only dopaminergic neurons has been fundamentally revised. It has been shown that, in addition to dopaminergic neurons, most of these centers contain neurons expressing one of the enzymes of dopamine synthesis: tyrosine hydroxylase (TH) or aromatic L-amino acid decarboxylase (AADC). We have obtained convincing evidence that in rats, the hypothalamic periventricular nucleus (PeVN) is one of the largest dopamine-rich centers, containing dopaminergic and monoenzymatic neurons. Indeed, using double immunostaining for TH and AADC, the PeVN was shown to contain almost three thousand dopaminergic and monoenzymatic neurons. According to high-performance liquid chromatography, PeVN contains L-DOPA and dopamine, which, apparently, are synthesized in monoenzymatic TH neurons and bienzymatic neurons, respectively. According to confocal microscopy, neurons (cell bodies, fibers), which were immunopositive only to TH, only to AADC, or both, are in close topographic relationships with each other and with the 3rd ventricle. These data suggest the mutual regulation of the neurons, as well as the delivery of dopamine and L-DOPA to the third ventricle, which is confirmed by their detection in the cerebrospinal fluid. Thus, evidence has been obtained that PeVN is one of the largest dopamine-rich centers of the brain, containing dopaminergic and monoenzymatic neurons. [ABSTRACT FROM AUTHOR]

Orthostatic hypotension (OH) is a common condition. Many potential etiologies of OH have been identified, but in clinical practice the underlying cause of OH is often unknown. In the present study, we identified a novel and extraordinary etiology of OH. We describe a first case of acquired severe OH with syncope, and the female patient had extremely low levels of catecholamines and serotonin in plasma, urine and cerebrospinal fluid (CSF). Her clinical and biochemical evidence showed a deficiency of the enzyme aromatic l -amino acid decarboxylase (AADC), which converts l -DOPA to dopamine, and 5-hydroxytryptophan to serotonin, respectively. The consequence of pharmacologic stimulation of catecholaminergic nerves and radionuclide examination revealed her catecholaminergic nerves denervation. Moreover, we found that the patient's serum showed presence of autoantibodies against AADC, and that isolated peripheral blood mononuclear cells (PBMCs) from the patient showed cytokine-induced toxicity against AADC. These observations suggest that her autoimmunity against AADC is highly likely to cause toxicity to adrenal medulla and catecholaminergic nerves which contain AADC, resulting in hypocatecholaminemia and severe OH. Administration of vitamin B6, an essential cofactor of AADC, enhanced her residual AADC activity and drastically improved her symptoms. Our data thus provide a new insight into pathogenesis and pathophysiology of OH. • This is a novel mechanism of idiopathic orthostatic hypotension. • Autoimmunity against Aromatic l -Amino Acid Decarboxylase (AADC) led to orthostatic hypotension (OH). • Autoimmunity caused toxicity to adrenal medulla and catecholaminergic nerves, and hypocatecholaminemia. • Anti-AADC autoantibody may be the hallmarks of this novel syndrome. • Administration of vitamin B6, an essential cofactor of AADC, improved symptoms. [ABSTRACT FROM AUTHOR]

Objectives: This exploratory research aimed to evaluate the levels of tryptophan hydroxylase 1 (TPH1) and aromatic l-amino acid decarboxylase (DDC), which play an important role in the serotonin synthesis pathway, in individuals with sleep bruxism (SB) diagnosed using audio–video polysomnography (vPSG) and compare them with that of individuals not presenting with SB. Materials and methods: The study included adult patients hospitalized in the Department and Clinic of Internal Medicine, Occupational Diseases, Hypertension and Clinical Oncology at the Wroclaw Medical University. The participants underwent a single-night vPSG for the evaluation of the SB parameters. Peripheral blood samples were also collected from them for estimating the serum levels of TPH1 and DDC. Results: A total of 105 patients (80 women and 25 men) were included in the study. All the patients were Caucasians and aged 18–63 years (mean age: 33.43 ± 10.8 years). Seventy-five patients (71.43%) presented with SB, of which 50 (47.62%) had severe SB, while the remaining 30 patients (28.57%) did not. No statistically significant differences in TPH1 and DDC levels were observed between the individuals with SB and without SB. A significant negative correlation was found between tonic SB episodes and DDC levels (p = 0.0012). Other correlations between the SB parameters and the levels of the studied enzymes were statistically insignificant (p > 0.05 for all comparisons). Conclusions: The levels of the enzymes that are crucial for serotonin synthesis (TPH1 and DDC) did not seem to influence SB. Clinical relevance: This study provides important insights for further research on the relationship between the serotonin pathway and SB, which should take into account not only the process of serotonin synthesis but also the effect of serotonin-dependent neurotransmission on SB. [ABSTRACT FROM AUTHOR]

Introduction: In gene therapy with adeno-associated virus (AAV) vectors for diseases of the central nervous system, the vectors can be administered into blood vessels, cerebrospinal fluid space, or the brain parenchyma. When gene transfer to a large area of the brain is required, the first two methods are used, but for diseases in which local gene transfer is expected to be effective, vectors are administered directly into the brain parenchyma., Areas Covered: Strategies for intraparenchymal vector delivery in gene therapy for Parkinson's disease, aromatic l-amino acid decarboxylase (AADC) deficiency, and epilepsy are reviewed., Expert Opinion: Stereotactic intraparenchymal injection of AAV vectors allows precise gene delivery to the target site. Although more surgically invasive than intravascular or intrathecal administration, intraparenchymal vector delivery has the advantage of a lower vector dose, and preexisting neutralizing antibodies have little effect on the transduction efficacy. This approach improves motor function in AADC deficiency and led to regulatory approval of an AAV vector for the disease in the EU. Although further validation through clinical studies is needed, direct infusion of viral vectors into the brain parenchyma is expected to be a novel treatment for Parkinson's disease and drug-resistant epilepsy.

This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l‐amino acid decarboxylase (AADC) deficiency and Parkinson's disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this brain structure. Additionally, the efficacy and safety of intraputaminal gene therapy demonstrate that restoration of dopamine synthesis in the putamen by using low doses of adeno‐associated viral vector serotype 2 to deliver the hAADC gene is well tolerated. This restoration leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous l‐DOPA into dopamine in Parkinson's patients. [ABSTRACT FROM AUTHOR]

This commentary provides an overview of the putamen as an established target site for gene therapy in treating aromatic l‐amino acid decarboxylase (AADC) deficiency and Parkinson’s disease, two debilitating neurological disorders that involve motor dysfunction caused by dopamine deficiencies. The neuroanatomy and the function of the putamen in motor control provide good rationales for targeting this brain structure. Additionally, the efficacy and safety of intraputaminal gene therapy demonstrate that restoration of dopamine synthesis in the putamen by using low doses of adeno‐associated viral vector serotype 2 to deliver the hAADC gene is well tolerated. This restoration leads to sustained improvements in motor and nonmotor symptoms of AADC deficiency and improved uptake and conversion of exogenous l‐DOPA into dopamine in Parkinson’s patients.

Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal-recessive neurometabolic disorder caused by variants in dopa decarboxylase (DDC) gene, resulting in a severe combined deficiency of serotonin, dopamine, norepinephrine, and epinephrine. Birth prevalence of AADCD varies by population. In pilot studies, 3- O -methyldopa (3-OMD) was shown to be a reliable biomarker for AADCD in high-throughput newborn screening (NBS) allowing an early diagnosis and access to gene therapy. To evaluate the usefulness of this method for routine NBS, 3-OMD screening results from the largest three German NBS centers were analyzed. A prospective, multicenter (n = 3) NBS pilot study evaluated screening for AADCD by quantifying 3-OMD in dried blood spots (DBS) using tandem mass spectrometry (MS/MS). In total, 766,660 neonates were screened from January 2021 until June 2023 with 766,647 with unremarkable AADCD NBS (766,443 by 1st-tier analysis and 204 by 2nd-tier analysis) and 13 with positive NBS result recalled for confirmatory diagnostics (recall-rate about 1:59,000). Molecular genetic analysis confirmed AADCD (c.79C > T p.[Arg27Cys] in Exon 2 und c.215 A > C p.[His72Pro] in Exon 3) in one infant. Another individual was highly suspected with AADCD but died before confirmation (overall positive predictive value 0.15). False-positive results were caused by maternal L-Dopa use (n = 2) and prematurity (30th and 36th week of gestation, n = 2). However, in 63% (n = 7) the underlying etiology for false positive results remained unexplained. Estimated birth prevalence (95% confidence interval) was 1:766,660 (95% CI 1:775,194; 1:769,231) to 1:383,330 (95% CI 1:384,615; 1:383,142). The identified child remained asymptomatic until last follow up at the age of 9 months. The proposed screening strategy with 3-OMD detection in DBS is feasible and effective to identify individuals with AADCD. The estimated birth prevalence supports earlier estimations and confirms AADCD as a very rare disorder. Pre-symptomatic identification by NBS allows a disease severity adapted drug support to diminish clinical complications until individuals are old enough for the application of the gene therapy. [ABSTRACT FROM AUTHOR]

Aromatic l-amino acid decarboxylases (AADCs) are ubiquitously found in higher organisms owing to their physiological role in the synthesis of neurotransmitters and alkaloids. However, bacterial AADC has not attracted much attention because of its rather limited availability and narrow substrate range. Here, we examined the biochemical properties of AADC from Bacillus atrophaeus (AADC-BA) and assessed the synthetic feasibility of the enzyme for the preparation of monoamine neurotransmitters. AADC-BA was expressed in Escherichia coli BL21(DE3) and the purified enzyme showed a specific activity of 2.6 ± 0.4 U/mg for 10 mM l-phenylalanine (l-Phe) at 37 °C. AADC-BA showed optimal pH and temperature ranges at 7–8 and 37–45 °C, respectively. The KM and kcat values for l-Phe were 7.2 mM and 7.4 s−1, respectively, at pH 7.0 and 37 °C. Comparison of the kinetic constants at different temperatures revealed that the temperature dependency of the enzyme was mainly determined by catalytic turnover rather than substrate binding. AADC-BA showed a broad substrate scope for various aromatic amino acids, including l-Phe, l-tryptophan (610% relative to l-Phe), l-tyrosine (12%), 3,4-dihydroxyphenyl-l-alanine (24%), 5-hydroxy-l-tryptophan (l-HTP, 71%), 4-chloro-l-phenylalanine (520%), and 4-nitro-l-phenylalanine (450%). Homology modeling and docking simulations were carried out and were consistent with the observed substrate specificity. To demonstrate the synthetic potential of AADC-BA, we carried out the production of serotonin by decarboxylation of L-HTP. The reaction yield of serotonin reached 98% after 1 h at the reaction conditions of 50 mM l-HTP and 4 U/mL AADC-BA. Moreover, we carried out preparative-scale decarboxylation of l-Phe (100 mM in 40-mL reaction mixture) and isolated the resulting 2-phenylethylamine (51% recovery yield). We expect that the broad substrate specificity of AADC-BA can be exploited to produce various aromatic biogenic amines. Key points: • AADC-BA showed broad substrate specificity for various aromatic amino acids. • The substrate specificity was elucidated by in silico structural modeling. • The synthetic potential of AADC-BA was demonstrated for the production of biogenic amines. [ABSTRACT FROM AUTHOR]

Prolactin (PRL) is a hormone principally secreted by lactotrophs of the anterior pituitary gland. Although the synthesis and exocytosis of this hormone are mainly under the regulation of hypothalamic dopamine (DA), the possibility that the anterior pituitary synthesises this catecholamine remains unclear. The present study aimed to determine if the anterior pituitary produces DA from the precursor l‐3,4‐dihydroxyphenylalanine (l‐dopa). Accordingly, we investigated the expression of aromatic l‐amino acid decarboxylase (AADC) enzyme and the transporter vesicular monoamine transporter 2 (VMAT2) in the anterior pituitary, AtT20 and GH3 cells by immunofluorescence and western blotting. Moreover, we investigated the production of DA from l‐dopa and its release in vitro. Then, we explored the effects of l‐dopa with respect to the secretion of PRL from anterior pituitary fragments. We observed that the anterior pituitary, AtT20 and GH3 cells express both AADC and VMAT2. Next, we detected an increase in DA content after anterior pituitary fragments were incubated with l‐dopa. Also, the presence of l‐dopa increased DA levels in incubation media and reduced PRL secretion. Likewise, the content of cellular DA increased after AtT20 cells were incubated with l‐dopa. In addition, l‐dopa reduced corticotrophin‐releasing hormone‐stimulated adrenocorticotrophic hormone release from these cells after AADC activity was inhibited by NSD‐1015. Moreover, DA formation from l‐dopa increased apoptosis and decreased proliferation. However, in the presence of NSD‐1015, l‐dopa decreased apoptosis and increased proliferation rates. These results suggest that the anterior pituitary synthesises DA from l‐dopa by AADC and this catecholamine can be released from this gland contributing to the control of PRL secretion. In addition, our results suggest that l‐dopa exerts direct actions independently from its metabolisation to DA. [ABSTRACT FROM AUTHOR]

Background: Aromatic l-amino acid decarboxylase (AADC) deficiency is an autosomal recessive metabolic disorder that results from disease-causing pathogenic variants of the dopa decarboxylase (DDC) gene. Loss of dopamine and serotonin production in the brain from infancy prevents achievement of motor developmental milestones.Methods: We retrospectively evaluated data obtained from requests to Medical Neurogenetics Laboratories for analyses of neurotransmitter metabolites in the cerebrospinal fluid, AADC enzyme activity in plasma, and/or Sanger sequencing of the DDC gene. Our primary objective was to estimate the prevalence of AADC deficiency in an at-risk population.Results: Approximately 20,000 cerebrospinal fluid samples were received with a request for neurotransmitter metabolite analysis in the eight-year study period; 22 samples tested positive for AADC deficiency based on decreased concentrations of 5-hydroxyindoleacetic acid and homovanillic acid, and increased 3-O-methyldopa, establishing an estimated prevalence of approximately 0.112%, or 1:900. Of the 81 requests received for plasma AADC enzyme analysis, 25 samples had very low plasma AADC activity consistent with AADC deficiency, resulting in identification of nine additional cases. A total of five additional patients were identified by Sanger sequencing as the primary request leading to the diagnosis of AADC deficiency.Conclusions: Overall, these analyses identified 36 new cases of AADC deficiency. Sequencing findings showed substantial diversity with identification of 26 different DDC gene variants; five had not previously been associated with AADC deficiency. The results of the present study align with the emerging literature and understanding of the epidemiology and genetics of AADC deficiency. [ABSTRACT FROM AUTHOR]

The tree shrew (Tupaia belangeri chinensis) is the closest living relative of primates. Yet, little is known about the anatomical distribution of tyrosine hydroxylase (TH)‐immunoreactive (ir) structures in the hypothalamus of the tree shrew. Here, we provide the first detailed description of the distribution of TH‐ir neurons in the hypothalamus of tree shrews via immunohistochemical techniques. TH‐ir neurons were widely distributed throughout the hypothalamus of tree shrew. The majority of hypothalamic TH‐ir neurons were found in the paraventricular hypothalamic nucleus (PVN) and supraoptic nucleus (SON), as was also observed in the human hypothalamus. In contrast, rare TH‐ir neurons were localized in the PVN and SON of rats. Vasopressin (AVP) colocalized with TH‐ir neurons in the PVN and SON in a large number of neurons, but oxytocin and corticotropin‐releasing hormone did not colocalize with TH. In addition, colocalization of TH with AVP was also observed in the other hypothalamic regions. Moreover, TH‐ir neurons in the PVN and SON of tree shrews expressed other dopaminergic markers (aromatic l‐amino acid decarboxylase and vesicular monoamine transporter, Type 2), further supporting that TH‐ir neurons in the PVN and SON were catecholaminergic. These findings provide a detailed description of TH‐ir neurons in the hypothalamus of tree shrews and demonstrate species differences in the distribution of this enzyme, providing a neurobiological basis for the participation of TH‐ir neurons in the regulation of various hypothalamic functions. [ABSTRACT FROM AUTHOR]

Abstract—The suprachiasmatic nucleus (SCN) regulates functions in accordance with circadian rhythms thanks to the pacemaker neurons present in it and afferents modulating their activity. One type of afferent is nerve fibers containing only tyrosine hydroxylase (TH) and secreting (L-dihydroxyphenylalanine) L-DOPA. The aim of this work was to test the hypothesis that L-DOPA comes from TH-containing fibers into neurons containing only aromatic L-amino acid decarboxylase (AAAD), where dopamine is synthesized. The synthesis of dopamine was evaluated by its content in SCN in intact rats on the 10th postnatal day (P10) and on P60, as well as by the total dopamine content in SCN and in the incubation medium after incubation of this nucleus in the medium with or without L-DOPA. It was shown that in intact rats SCN contains dopamine at the same concentration at P10 and P60. Some of the experiments with incubation of SCN slices were performed with rats injected with neurotoxins of monoaminergic neurons to exclude the synthesis of dopamine from L-DOPA in monoaminergic structures. At P10, during incubation of SCN in L-DOPA-containing medium, an increase in dopamine synthesis was observed equally in animals in control (normal) and after exposure to neurotoxins, which indicates synthesis of dopamine only in monoenzymatic AAAD-containing neurons. In a similar experiment at P60, the addition of L-DOPA into the incubation medium also led to an increase in the synthesis of dopamine, however, in animals exposed to neurotoxins to a lesser extent than in the control. This means that in adult animals, dopamine is synthesized in SCN mainly in monoenzymatic AAAD-containing neurons and to a lesser extent in monoaminergic structures. Thus, it was shown that dopamine in SCN is synthesized in monoenzymatic AAAD-containing neurons from L-DOPA secreted by monoenzymatic TH-containing fibers. [ABSTRACT FROM AUTHOR]

Since the late 80s it has been repeatedly shown that besides dopaminergic neurons, the brain contains so-called monoenzymatic neurons possessing one of the enzymes of dopamine (DA) synthesis, tyrosine hydroxylase (TH) or aromatic l-amino acid decarboxylase (AADC). However, the data on the existence of monoenzymatic neurons in the striatum remain controversial, and little is known about their functional significance. The aim of this study was to test our hypothesis that monoenzymatic TH-containing neurons produce DA in cooperation with the neurons containing AADC, which might help to compensate DA deficiency under the failure of the nigrostriatal dopaminergic system. Using a combination of techniques: retrograde tracing, qPCR and immunolabeling for TH, AADC and MAP2, we showed that the striatum of mice with normal and degraded dopaminergic system comprises of monoenzymatic TH- and AADC-containing neurons. To provide evidence for cooperative synthesis of DA, we used an ex vivo model of inhibiting of DA synthesis by blocking transport of l-DOPA, produced in monoenzymatic TH-containing neurons, to neurons containing AADC by means of l-leucine, a competitive inhibitor of the membrane transporter of large neutral amino acids, and l-DOPA. With this original approach, cooperative synthesis of DA in the striatum was proven in MPTP-treated mice but not in the control. Furthermore, we demonstrated that the proportion of DA produced through cooperative synthesis in the striatum of MPTP-treated mice increases as the degradation of dopaminergic system proceeds. An increase in the proportion of cooperative synthesis of DA alongside degradation of the dopaminergic system is also proved by an increase of both TH gene expression and the number of TH-immunoreactive structures in the striatum. Thus, these data suggest that the cooperative synthesis of DA in the degraded striatum is an up-regulated compensatory reaction, which plays an increasing role as DA deficiency rises, and might be considered among the principal mechanisms of neuroplasticity in neurodegenerative diseases.

Parkinson's disease (PD) is a neurodegenerative illness characterized by specific loss of dopaminergic neurons, resulting in impaired motor movement. Its prevalence is twice as compared to the previous 25 years and affects more than 10 million individuals. Lack of treatment still uses levodopa and other options as disease management measures. Treatment shifts to gene therapy (GT), which utilizes direct delivery of specific genes at the targeted area. Therefore, the use of aromatic L-amino acid decarboxylase (AADC) and glial-derived neurotrophic factor (GDNF) therapy achieves an effective control to treat PD. Patients diagnosed with PD may experience improved therapeutic outcomes by reducing the frequency of drug administration while utilizing provasin and AADC as dopaminergic protective therapy. Enhancing the enzymatic activity of tyrosine hydroxylase (TH), glucocorticoid hormone (GCH), and AADC in the striatum would be useful for external L-DOPA to restore the dopamine (DA) level. Increased expression of glutamic acid decarboxylase (GAD) in the subthalamic nucleus (STN) may also be beneficial in PD. Targeting GDNF therapy specifically to the putaminal region is clinically sound and beneficial in protecting the dopaminergic neurons. Furthermore, preclinical and clinical studies supported the role of GDNF in exhibiting its neuroprotective effect in neurological disorders. Another Ret receptor, which belongs to the tyrosine kinase family, is expressed in dopaminergic neurons and sounds to play a vital role in inhibiting the advancement of PD. GDNF binding on those receptors results in the formation of a receptor-ligand complex. On the other hand, venous delivery of recombinant GDNF by liposome-based and encapsulated cellular approaches enables the secure and effective distribution of neurotrophic factors into the putamen and parenchyma. The current review emphasized the rate of GT target GDNF and AADC therapy, along with the corresponding empirical evidence., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Total RNA from human hair follicles was reverse transcribed and amplified using primers specific for aromatic L-amino acid decarboxylase (AADC) and tyrosine hydroxylase (TH). Agarose electrophoresis of the amplified products showed reverse transcription polymerase chain reaction (RT-PCR) products of the expected size for both TH and AADC. Sequencing showed that the amplified products matched the known sequences of TH and AADC. This study identifies hair follicles as a convenient, uninvasive, source of the mRNA for TH and AADC. Analysis of these mRNA's may be useful in the diagnosis and investigation of conditions resulting from qualitative changes in the genes that code for these enzymes.

Monoamine neurotransmitters play an important role in the modulation of sensory, motor and autonomic functions in the spinal cord. Although traditionally it is believed that in mammalian spinal cord, monoamine neurotransmitters mainly originate from the brain, accumulating evidence indicates that especially when the spinal cord is injured, they can also be produced in the spinal cord. In this review, I will present evidence for a possible pathway for two-step synthesis of dopamine and serotonin in the spinal cord. Published data from different sources and unpublished data from my own ongoing projects indicate that monoenzymatic cells expressing aromatic L-amino acid decarboxylase (AADC), tyrosine hydroxylase (TH) or tryptophan hydroxylase (TPH) are present in the spinal cord and that these TH and THP cells often lie in close proximity to AADC cells. Prompted by the above evidence, I hypothesize that dopamine and serotonin could be synthesized sequentially in two monoenzymatic cells in the spinal cord via a TH-AADC and a TPH-AADC cascade respectively. The monoamines synthesized through this pathway may compensate for lost neurotransmitters following spinal cord injury and also may play specific roles in the recovery of sensory, motor and autonomic functions.

Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. Keywords: AADC deficiency; DDC; gene therapy; genetics; aromatic L-amino acid decarboxylase EN AADC deficiency DDC gene therapy genetics aromatic L-amino acid decarboxylase 737 738 2 08/05/22 20220801 NES 220801 Pearson TS, Gupta N, San Sebastian W, et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. [Extracted from the article]

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare inherited disorder that affects neurotransmitter biosynthesis. A DDC founder mutation c.714 + 4A > T (IVS6 + 4A > T) is prevalent in the Chinese population. This study investigated the epidemiology of AADC deficiency in Taiwan by analyzing data from National Taiwan University Hospital (NTUH), a central institution for diagnosing and treating the disease. From January 2000 to March 2023, 77 patients with AADC deficiency visited NTUH. Among them, eight were international patients seeking a second opinion, and another two had one or both non-Chinese parents; all others were ethnically Chinese. The c.714 + 4A > T mutation accounted for 85% of all mutated alleles, and 94% of patients exhibited a severe phenotype. Of the 77 patients, 31 received gene therapy at a mean age of 3.76 years (1.62-8.49) through clinical trials, and their current ages were significantly older than those of the remaining patients. Although the combined incidence of AADC deficiency in this study (1:66491 for 2004 and later) was lower than that reported in newborn screening (1:31997 to 1:42662), case surges coincided with the launch of clinical trials and the implementation of newborn screening. Currently, many young patients are awaiting for treatment., Competing Interests: Wuh‐Liang Hwu participated as an advisory board member, received consulting fees, and was a speaker for PTC Therapeutics. In addition, he was a grant recipient for PTC Therapeutics and a research investigator for PTC Therapeutics. Rai‐Hseng Hsu, Mei‐Hsin Li, Hui‐Min Lee, Hui‐An Chen, Ni‐Chung Lee, and Yin‐Hsiu Chien declare no conflict of interest., (© 2023 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)