CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 11, Issue 4, 2012

The Society for the Study of Neuroprotection and Neuroplasticity (SSNN) was created in 2005 by an international group of clinicians and basic scientists under the initiative of Prof. Dafin F. Muresanu, University of Medicine and Pharmacy “Iuliu Hatieganu”, Cluj-Napoca, Romania. The SSNN is a scientific organization focusing on basic and clinical research, whose goal is to create a discussion platform to facilitate our understanding of endogenous basic biological processes together with the development of pharmacological and non-pharmacological strategies for positive manipulation of neurotrophicity, neuroprotection, neuroplasticity and neurogenesis. The Society subsequently became an affiliated organ of the Global College of Neuroprotection and Neuroregeneration (GCNN), founded in 2004 by Russell Pendleton, London, UK and Hari Shanker Sharma, Uppsala, Sweden. Dubrovnik, a Croatian city on the suggestive Adriatic Sea coast, and among UNESCO's list of World Heritage Sites, was the venue for this year's annual meeting of the SSNN. The themes covered include brain protection and recovery, dementia, neurorehabilitation, and traumatic brain injury. There is increasing evidence that cerebrovascular dysfunction plays a role in vascular causes of cognitive impairment and also in Alzheimer's disease. Vascular dementia can be viewed as a heterogeneous cluster of different syndromes and disorders with cognitive deficit, and whose treatment is a challenging issue. Data were presented suggesting that one approach to this problem may be the use of a suitable combination of neurotrophic factors/peptides, in a brain-penetrant form, for example Cerebrolysin (neurotrophic peptidergic mixture produced by standardized enzymatic breakdown of lipid-free porcine brain proteins), which has been documented to attenuate central nervous system pathologies following traumatic or metabolic insults to the brain or spinal cord. Is “senile dementia of the Alzheimer type” the result of a combination of several processes, operating differently in each individual? It was suggested that perhaps Alzheimer's disease should more correctly be regarded as a syndrome which can result from many different etiologies, some genetic but mostly environmental (risk factors such as hypertension, hypercholesterolemia, metabolic disease, smoking, and obesity). As such, combating dementia should begin in midlife, not in old age. Neurorehabilitation is a speciality of neuroscience, which deals with the study and application of complex medical processes aiming at recovery from nervous system injury and to compensate for functional alterations. Beside the use of training techniques and other behavioral interventions, neurological rehabilitation can be promoted by the use of pharmacological agents. In addition to pharmacological treatments for risk factors such as hypertension and hyperlipidemia and secondary prevention, drugs can also be used to facilitate brain recovery. The utilization of particular drugs for neuroprotection and brain repair was discussed, along with the concept of mono- vs multimodal action. Positive data from a recent multicenter stroke trial with Cerebrolysin were also presented. Traumatic brain injury (TBI), also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI is a major cause of death and disability worldwide, especially in children and young adults. In addition to the damage caused at the moment of injury, brain trauma causes secondary injury, a variety of events that take place in the minutes and days following the injury. These processes, which include alterations in cerebral blood flow and pressure within the skull, contribute substantially to damage from the initial injury. An important diagnostic aspect of TBI today includes imaging techniques such as computed tomography and magnetic resonance imaging; for the latter, novel methods to measure cerebrovascular reactivity non-invasively show promise for identifying vascular endophenotypes in TBI. Diffusion Tensor Imaging shows encouraging development as a tool to measure diffuse axonal injury, which is a prominent mechanism of TBI. Up-and-coming quantitative volumetric methods allow detection of regional changes in brain structure after TBI, and identify brain regions which are particularly susceptible to diffuse traumatic insults. Depending on the injury, treatment required may be minimal or may include interventions such as medications and emergency surgery. Approaches to restorative treatment in experimental models of TBI were discussed, including the use of cell-based therapy, and pharmacological therapies comprising erythropoietin, statins, Thymosin B4 and Cerebrolysin. These treatments promote brain remodeling and thereby enhance neurological and cognitive outcomes. Moreover, magnetic resonance imaging can be used as an index to monitor restorative response. Contrary to what was once believed, we are now coming to appreciate that nervous system repair and neurorestoration is an accomplishable goal. To paraphrase the English biologist Thomas Henry Huxley (1825 - 1895): “The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.”

Pain is a fundamental experience characterized by an unpleasant physical perception and corresponding emotional state. Disease or trauma affecting the peripheral or central neuronal sensory pathway can produce a form of chronic pain known as neuropathic pain. This pain may occur with central nervous system disorders, such as stroke or multiple sclerosis, or with conditions associated with peripheral nerve damage, such as diabetic neuropathy or viral infection. It can also be induced by mechanical trauma or by neurotoxic chemicals (for example, chemotherapeutics). The control of pain has been a major goal of pharmacotherapy from the earliest times; however, effective management of both acute and chronic pain remains suboptimal. The situation is particularly challenging for chronic pain and neuropathic pain sufferers, for which there is a high unmet need. Indeed, it is estimated that only one in four patients experience over 50% pain relief [1]. One of the major reasons why pain relief remains such a challenge is the robust inter-individual variability that exists in sensitivity to pain and the response to analgesics [2]. Much of the variability in chronic pain and analgesic response is heritable, yet an understanding of the genetic determinants underlying this variability is far from complete. In a study just published by Sorge and colleagues (2012), the authors show that variation within the coding sequence of the gene encoding the P2X7 receptor (P2X7R) affects chronic pain sensitivity in both mice and humans. P2X receptors function as ATP-gated nonselective ion channels permeable to Na+, K+, and Ca2+. The P2X7R is rather unusual among the P2X receptor family in that sustained activation by extracellular ATP causes the formation of a reversible plasma membrane pore permeable to molecules with a mass of up to 900 Da [3]. Specifically these authors made use of genome-wide linkage analyses to identify an association between nerve-injury-induced pain behavior (mechanical allodynia) and the P451L mutation of the mouse P2rx7R gene. Mice bearing P2X7Rs having impaired pore formation showed less allodynia than mice with the pore-forming P2rx7 allele. Administration of a peptide corresponding to the P2X7R C-terminal domain, which blocked pore formation but not cation channel activity, selectively reduced nerve injury and inflammatory allodynia only in mice with the pore-forming P2rx7 allele. Importantly, in independent human chronic pain cohorts (mastectomy and osteoarthritis), a genetic association between lower pain intensity and the hypofunctional His270 (rs7958311) allele of P2X7R was observed. Currently available drugs for neuropathic pain include antidepressants, anticonvulsants, sodium channel blockers, N-methyl-Daspartate receptor antagonists, and opioids. Unfortunately, these drugs were designed to hit neuronal targets and focus on blocking neurotransmission. They can treat pain symptoms but not the underlying pathology of neuropathic pain. Further, they only provide a transient relief of neuropathic pain in only a fraction of patients and produce severe CNS side effects. From their findings, Sorge et al. (2012) posit that selectively targeting P2X7R pore formation while leaving cation channel activity intact could provide a preferred strategy for reducing pain in individuals who carry P2X7R haplotypes that confer a high risk for chronic pain.

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Cell replacement therapies are an attractive mode of treatment for neurodegenerative disorders as they have the potential to alleviate or modify disease symptoms and restore function. In Parkinson's disease, the cell type requiring replacement is dopamine-producing neurons of the midbrain. The source of replacement cells is contentious, with opinion still evolving. Clinical trials have previously used fetal brain tissue; however, this will likely be superseded by the use of embryonic or induced pluripotent stem cells, due to their greater availability and homogeneity. One significant caveat in the use of any cell source for therapy is that cells must first be adequately characterised and purified. The gold standard marker in the identification of dopaminergic neurons is tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, catalyzing the conversion of L-tyrosine to L-3,4-dihydroxyphenylalanine. However, there are multiple ways of measuring TH readout, and potential flaws in the fidelity of TH expression. This review will look at the complex regulatory mechanisms that govern different facets of TH expression, including reported differences in TH expression in vitro and in vivo. We will also examine the regulation of the TH gene; assessing the which, the where and the when of TH expression. We will look at how knowledge of regulation of the TH gene can be utilised to enhance research efforts. And, finally we will delve into the transcription factors that govern elements of TH expression, and which may prove more effective for defining appropriate dopaminergic neuron precursor cells.

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in brain catecholamine biosynthesis, and tetrahydrobiopterin is its cofactor. Research has focused on identifying mechanisms of TH activity regulation. TH activity is modulated by the cofactor itself, and is enhanced by several kinases phosphorylating key serines in the TH regulatory domain. Aside from these, the mechanisms that control TH gene transcription and TH mRNA translation are also related with the regulation of TH activity. Parkinson's disease (PD) is characterized by severe loss of dopaminergic neurons and depletion of dopamine in substantia nigra. Reduction of TH expression results in diminished dopamine synthesis and leads to PD; thus TH is essential in the pathogenesy of PD. It has also been shown that dysregulation of TH activity will contribute to PD. For example, α-synuclein represses TH not only by inhibiting phosphorylation at Ser40 of TH, but also by stimulating protein phosphatase 2A activity, which decreases dopamine synthesis and leads to parkinsonism. Based on these studies of TH in PD pathogenesis, a therapeutic strategy aimed to improve striatal TH expression in PD has received wide interest. Evidence shows that using drugs or other treatment methods such as gene replacement therapy to increase nigrostriatal TH expression is an effective therapy for PD. Further investigation of TH regulatory mechanisms will not only provide additional drug targets for PD, but may also help to identify new PD therapeutics.

The nigrostriatal pathway is very likely involved in sleep regulation, considering the occurrence and high prevalence of sleep-related disorders in patients with Parkinson's disease. Indeed, dopaminergic neurons in the ventral tegmental area were recently shown to fire in bursts during paradoxical sleep (PS), but little is known about the activity of the nigrostriatal dopamine (DA) cells in relation to PS. In view of that we hypothesized that paradoxical sleep deprivation (PSD) may play a relevant role in nigrostriatal tyrosine hydroxylase (TH) expression and, subsequently, in sleep rebound. The present study was designed to determine the effects of PSD in the nigrostriatal pathway in mice by means of neurochemical and behavioral approaches. Intraperitoneal reserpine (1 mg/kg) associated to α-methyl-p-tyrosine (αMT) (250 mg/kg) to produce catecholamine depletion, or rotenone (10 mg/kg) to increase striatal DA turnover were injected 30 min before the 24 h of PSD. Catalepsy and open-field tests indicated that motor deficits induced by reserpine-αMT were counteracted by PSD, which, in contrast, potentiated the motor impairment induced by rotenone. Besides, PSD produced down-regulation on TH expression within the substantia nigra pars compacta and striatum, without affecting the number or the optical density of dopaminergic neurons present in the respective areas. Interestingly, PSD potentiated the downregulation of TH expression in the substantia nigra pars compacta and striatum induced by the co-administration of reserpine-αMT. These results reinforce the notion of a strong participation of DA in PS, as a consequence of the modulation of TH protein expression in the nigrostriatal pathway.

Parkinson's disease (PD) is characterized by the progressive loss of the dopaminergic neurons leading to decrease in striatal dopamine (DA) levels. In the present review, our focus was on recent advances in the treatment procedures of PD to achieve an increase in deficient tyrosine hydroxylase (TH) activity and/or expression. Stimulation of residual TH activity by the cofactors, 6R-L-erythro-tetrahydrobiopterin (BPH4) or NADH, or by brain transplant of natural TH-containing cells (fetal substantia nigra) or genetically engineered TH-containing cells, has been tried experimentally and clinically lately. As a promising approach to the gene therapy, intrastriatal expression of DAsynthesizing enzymes through transduction with separate adeno-associated virus (AAV) vectors/ marrow stromal cells (MSCs) or nonviral intravenous administration of rat transferrin receptor monoclonal antibody (TfRmAb)-targeted PEGylated immunoliposomes (PILs) has been found to be effective in animal models. Oxidative stress has been identified as one of the intermediary risk factors that could initiate and/or promote degeneration of DA neurons. TH itself is a prime target of oxidative/nitrosative injury. Certain superoxide dismutase and catalase mimetic prevented nitration of TH in cultured dopaminergic neurons. Therefore, development of therapeutic agents that can prevent formation of or specifically remove nitrating agents without interfering with normal neuronal function may protect protein from inactivation and provide means of limiting neuronal injury in PD. Non-pharmacological approaches such as diet therapy or use of active constituents of plants and phytomedicines have also emerged as a new - area of high interest. New treatment strategies for TH dysfunction rectification, a provision for neuroprotection in PD, seem to be on the horizon with many therapies under investigation.

Tyrosine hydroxylase (TH) is the rate limiting step in the biosynthesis of dopamine and other catecholamines. Differences have been noted in concentration and availability of this enzyme and its cofactors in disease states such as Parkinson's disease (PD) which are subject to alterations in catecholamines. More evidence suggests in fact that TH may play a direct role in the pathogenesis of PD, especially through oxidative stress and pro-inflammatory mechanisms. Treatment for PD has classically involved maximizing endogenous dopamine by medicinal options that either replace dopamine or augment the dopaminergic pathway. The medications are unfortunately limited, given they are not curative and involve potential short-term and long-term side effects. Gene therapy in PD is a burgeoning field which provides a way to augment dopamine production, and potentially protect the dopaminergic neurons from further degeneration. Given its importance in dopamine catabolism and the possibility that it may contribute to pathogenesis, TH is one target of gene therapy. Further research into the regulatory mechanisms and function of TH are promising in improving gene therapy approaches as well as other treatment modalities.

Neurodegenerative Parkinson's disease (PD) is a multifactorial disorder; effects like alpha synuclein aggregation, low dopamine levels and dopaminergic neurodegeneration are considered to be hallmarks of the disease. Several recent studies have pointed towards an important role of enzyme tyrosine hydroxylase (TH) in the pathophysiology of PD. We embarked on the present studies to explore the mechanistic role of C. elegans gene cat-2, a putative tyrosine hydroxylase, in PD. Utilizing the powerful genetic model system C. elegans, which has previously provided critical understanding of several human diseases, we employed a reverse genetics approach via RNAi mediated gene silencing of cat-2, to study various disease related effects in three different transgenic strains of the nematode. Knocking-down of cat-2 led to increase in aggregation of alpha synuclein, as was studied via expression of YFP. Similarly the silencing of cat-2 had significant effects on associated endpoints including oxidative stress, lipid content and neurotransmission; exemplifying the role of cat-2, the putative tyrosine hydroxylase, in Parkinsonism of the nematode model. The findings are significant as this model could further be used to study the entire associated pathway in greater detail and with the advantages that the model system C. elegans presents, the knockdown of cat-2 in the alpha synuclein expressing strain, could be employed for screening potential pharmacological agents targeted at TH which could lead to designing of possible therapeutic interventions for the disease.

Parkinson's disease (PD) is a common chronic progressive neurodegenerative disorder in elderly people. A consistent neurochemical abnormality in PD is degeneration of dopaminergic neurons in substantia nigra pars compacta, leading to a reduction of striatal dopamine (DA) levels. As tyrosine hydroxylase (TH) catalyses the formation of Ldihydroxyphenylalanine (L-DOPA), the rate-limiting step in the biosynthesis of DA, the disease can be considered as a TH-deficiency syndrome of the striatum. Problems related to PD usually build up when vesicular storage of DA is altered by the presence of either α-synuclein protofibrils or oxidative stress. Phosphorylation of three physiologically-regulated specific sites of N-terminal domain of TH is vital in regulating its kinetic and protein interaction. The concept of physiological significance of TH isoforms is another interesting aspect to be explored further for a comprehensive understanding of its role in PD. Thus, a logical and efficient strategy for PD treatment is based on correcting or bypassing the enzyme deficiency by the treatment with L-DOPA, DA agonists, inhibitors of DA metabolism or brain grafts with cells expressing a high level of TH. Neurotrophic factors are also attracting the attention of neuroscientists because they provide the essential neuroprotective and neurorestorative properties to the nigrostriatal DA system. PPAR-γ, a key regulator of immune responses, is likewise a promising target for the treatment of PD, which can be achieved by the use of agonists with the potential to impact the expression of pro- and anti-inflammatory cytokines at the transcriptional level in immune cells via expression of TH. Herein, we review the primary biochemical and pathological features of PD, and describe both classical and developing approaches aimed to ameliorate disease symptoms and its progression.

Although researchers are pursuing “disease modifying” medications to slow or stop Parkinson's disease (PD) progression, a myriad of agents with protective properties in cell cultures and animal models have yielded few treatments in clinical practice. Developing safe and effective treatments with disease-modifying/neuroprotective mechanisms of action and identifying patients in the pre-motor phase will be a challenge. The implication of tyrosine hydroxylase (TH), the enzyme that catalyzes the formation of L-3,4-dihydroxyphenylalanine, in the pathogenesis of PD at different levels makes it a promising candidate for developing efficient treatment based on correcting or bypassing the enzyme deficiency. TH is also the key enzyme for immunorreactivity in PD models and is used to assess the efficacy of novel diseasemodifying medications. PD animal models are genetic: alpha-synuclein models, parkin (PINK 1 and DJ1) and leucine-rich repeat kinase 2 or pharmacological and neurotoxic: reserpine, 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, rotenone, paraquat/maneb, and trichloroethylene. This review is focused on the state of art of PD models, the relationship with TH, and potential neuroprotective agents to treat PD. The latter include gene therapy, transplantation, erythropoietin, natural phenolic compounds, doxycycline, ethyl pyruvate, 9-methyl-beta-carboline, vascular endothelial growth factor, simvastatin, zonisamide, modafinil, melatonin, cannabinoids, rottlerin, fluoxetine, paroxetine, coenzyme Q10, N-acetylcysteine and vaccines like Bacille Calmette-Guerin, with different proposed mechanisms of action. Also of note is the link between hypovitaminosis D and neurodegeneration opening new perspectives in research with TH genes and PD models treated with vitamin D. Translational scientists can contribute to a better understanding of the pathogenesis of PD and lead to more effective treatments.

Oxidant molecules generated during neuronal metabolism appear to play a significant role in the processes of aging and neurodegeneration. Increasing experimental evidence suggests the noteworthy relevance of the intracellular reduction-oxidation (redox) balance for the dopaminergic (DA-ergic) neurons of the substantia nigra pars compacta. These cells possess a distinct physiology intrinsically associated with elevated reactive oxygen species production, conferring on them a high vulnerability to free radical damage, one of the major causes of selective DA-ergic neuron dysfunction and degeneration related to neurological disorders such as Parkinson's disease. Tyrosine hydroxylase (tyrosine 3-monooxygenase; E.C. 1.14.16.2; TH) activity represents the rate-limiting biochemical event in DA synthesis. TH activity, metabolism and expression are finely tuned by several regulatory systems in order to maintain a crucial physiological condition in which DA synthesis is closely coupled to its secretion. Alterations of these regulatory systems of TH functions have indeed been thought to be key events in the DA-ergic degeneration. TH has seven cysteine residues presenting thiols. Depending on the oxido-reductive (redox) status of the cellular environment, thiols exist either in the reduced form of free thiols or oxidized to disulfides. The formation of disulfides in proteins exerts critical regulatory functions both in physiological and in pathological conditions when oxidative stress is sustained. Several reports have recently shown that redox state changes of thiol residues, as consequence of an oxidative injury, can directly or indirectly affect the TH activity, metabolism and expression. The major focus of this review, therefore, is to report recent evidence on the redox modulation of TH activity and expression, and to provide an overview of a cellular phenomenon that might represent a target for new therapeutic strategies against the DA-ergic neurodegenerative disorders.

Parkinson's disease (PD) is related to excess production of reactive oxygen species (ROS) or inadequate and impaired detoxification by endogenous antioxidants, alterations in catecholamine metabolism, alterations in mitochondrial electron transfer function, and enhanced iron deposition in the substantia nigra. The concept that oxidative stress is an important mechanism underlying the degeneration of dopaminergic (DAergic) neurons is reinforced by data documenting that high levels of lipid peroxidation, increased oxidation of proteins and DNA and depletion of glutathione are observed in postmortem studies of brain tissues of PD patients. Tyrosine hydroxylase (TH) is an important neuronal enzyme that, in the presence of tetrahydrobiopterin, catalyzes the initial and rate-limiting step in the biosynthesis of the catecholamine neurotransmitters dopamine (DA) and norepinephrine, and is frequently used as a marker of DAergic neuronal loss in animal models of PD. The role for TH as generators of ROS are highly relevant to PD because ROS have been proposed to contribute to the neurodegeneration of DA neurons. Oxidants and superoxide radicals are produced as byproducts of oxidative phosphorylation, making mitochondria the main site of ROS generation within the cell and the site of the first line of defence against oxidative stress. ROS can affect mitochondrial DNA (mtDNA) causing modulation in synthesis of electron transport chain (ETC) components, decreased ATP production, and increased leakage of ROS.

Classically, Parkinson's disease (PD) is considered to be a motor system affliction and its diagnosis is based on the presence of a set of cardinal motor signs (e.g. rigidity, bradykinesia, rest tremor and postural reflex disturbance). However, there is considerable evidence showing that non-motor alterations (e.g. anxiety, depression, sleep, gastrointestinal and cognitive functions) precede the classical motor symptoms seen in PD. The management of these nonmotor symptoms remains a challenge. A pattern of regional neurodegeneration that varies considerably depending upon the neuronal population affected may explain the different symptoms. In fact, differential mechanisms of neuronal vulnerability within the substantia nigra pars compacta (SNpc) suggests that factors other than location contribute to the susceptibility of these neurons. In this review we discuss how these factors interact to ultimately target the SNpc. Remarkably, this region consists of approximately 95% of the tyrosine hydroxylase (TH)-immunoreactive neurons in both human and rat brains, and consequently this implicates elevated levels of dopamine metabolites, free radicals and other hazard species in these neurons. An understanding of how these factors promote neuronal death may be useful for the development of novel neuroprotective and/or neurorestorative strategies for PD.

Tyrosine hydroxylase (TH) is the rate limiting enzyme responsible for converting tyrosine to L-DOPA in the dopamine synthesis pathway. The pathophysiology of Parkinson's disease (PD) is largely due to the nigrostriatal dopaminergic system, with a decrease in TH activity, TH synthesis and TH mRNA in the striatum of PD and animal experimental models. TH is thus one of the main targets for gene therapy in PD. TH activity variations during L-DOPA and new antiparkinsonian treatments have been extensively studied. Pharmacological trials with neuroprotective treatments could modify these variations, suggesting a direct involvement of TH cells in the neurodegenerative process. α- Synuclein, the main component of Lewy bodies regulates the production of dopamine through its interaction with TH. Over-expression of α-synuclein reduces the levels of TH mRNA and protein in the brain and in this way links the histological description of PD and its pathological biochemistry.

Parkinson's disease (PD) is associated with neurodegeneration of the nigrostriatal tract and is accompanied with loss of tyrosine hydroxylase (TH) and dopamine (DA). Development of neuroprotective strategies targeting PD is often undermined by lack of proper understanding of processes contributing to the pathology. In this mini review we have tried to briefly outline the involvement of TH and α-synuclein in PD. Aberrant expression of α-synuclein is toxic to dopaminergic neurons. It interacts with ubiquitin-proteasomal processing system, implicated in oxidative injury and mitochondrial dysfunction which ultimately induce neurodegenration and cell death. The contributions of DJ-1 in TH regulation have also been discussed. Brain specific TH expression with the combined use of the pegylated immunoliposome (PILs) gene transfer technology and brain specific promoters as a new approach to treat PD has also been included.

Parkinson's disease is a major age-related neurodegenerative disorder. As the classical disease-related motor symptoms are associated with the loss of dopamine-generating cells within the substantia nigra, tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of catecholamines has become an important target in the development of Parkinson's disease drug candidates, with the focus to augment TH levels or its activity. By contrast, TH inhibitors are of relevance in the treatment of conditions associated with catecholamine over-production, as occurs in pheochromocytomas. To aid characterizing new drug candidates, a molecular docking study of catecholamines and a novel hypothetical compound [4-(propan-2-yl) phenyl]carbamic acid (PPCA) with TH is described. Docking was performed using Autodock4.2 and results were analyzed using Chimera1.5.2. All the studied ligands were found to bind within a deep narrow groove lined with polar aromatic and acidic residues within TH. Our results corroborated a ‘hexa interacting amino acids unit’ located in this deep narrow groove crucial to the interaction of PPCA and the studied catecholamines with TH, whereby the ‘His361-His336 dyad’ was found to be even more crucial to these binding interactions. PPCA displayed a binding interaction with human TH that was comparable to the original TH substrate, L-tyrosine. Hence PPCA may warrant in vitro and in vivo characterization with TH to assess its potential as a candidate therapeutic.

The tyrosine hydroxylase (TH) gene encodes a monoxygenase that catalyzes the rate limiting step in dopamine biosynthesis. A hallmark of Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra. Consistent with the essential role of TH in dopamine homeostasis, missense mutations in both alleles of TH have been associated with severe Parkinsonism-related phenotypes including infantile Parkinsonism. It has been speculated for a long time that genetic variants in the TH gene modify adult-onset PD susceptibility but the answer has not been clear. Genetic variants (both sequence variations and structural variations) can be classified into three categories based on their relative frequency in population: common variants (polymorphisms), rare variants and mutations. Each of these factors has a different mode in influencing the genetic risk and often requires different approaches to decipher their contributions to the disease. In the past few years, the revolutionary advances in genomic technology have allowed systematic evaluations of these genetic variants in PD, such as the genome-wide association study (GWAS, to survey common variants), copy number variation analysis (to detect structural variations), and massive parallel next generation sequencing (to detect rare variants and mutations). In this review, we have summarized the latest evidence on TH genetic variants in PD, including our ongoing effort of using whole exome sequencing to search for rare variants in PD patients.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are two debilitating health disorders afflicting millions worldwide. Recent research has revealed similarities between AD and T2DM. Both these protein conformational disorders are associated with obesity, insulin resistance, inflammation and endoplasmic reticulum stress, en-route initiation and/or stage aggravation. In this mini review we have tried to summarize studies describing obesity, insulin resistance and glucocorticoid imbalance as common patho-mechanisms in T2DM and AD. A reduction in tyrosine hydroxylase (TH) in the brain has been found to occur in Parkinson's disease (PD). AD, T2DM and PD share common risk factors like depression. Thus, whether TH is involved in the ‘state of cognitive depression’ that is the hallmark of AD and often accompanies PD and T2DM is also explored.