Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The introduction of L-Dopa has been a landmark in Neuroscience. Before the use of L-Dopa, Parkinson's disease (PD) was considered a disabling disease with no effective treatment. The development of L-Dopa followed a rationale approach: first, the discovery of dopamine deficiency in the striatum of patients with PD; and then the use of precursor of dopamine. Overall, the whole process took less than 12 years; this is a remarkable short time taking into account that the development of a similar crucial drug such as insulin took 50 years. In addition, the success of L-Dopa stimulated the neurochemistry research for all neurodegenerative diseases.
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PMID:[Short history of L-Dopa]. 1194 Apr 9

Insulin resistance is known to play a pivotal role in type 2 diabetes. Senile individuals, besides being prone to insulin resistance and, consequently, to type 2 diabetes, manifest diseases of the central nervous system (CNS) that may be influenced by disturbances of insulin signaling in the brain, such as memory impairment, Parkinson disease, and Alzheimer disease. We investigated the expression and response to insulin of elements involved in the insulin-signaling pathway in the forebrain cortex and cerebellum of rats ages 1 d to 60 wk. The protein content of insulin receptors and SRC homology adaptor protein (SHC) did not change significantly along the time frame analyzed. However, insulin-induced tyrosine phosphorylation of the insulin receptor and SHC, and the association of SHC/growth factor receptor binding protein-2 (GRB2) decreased significantly from d 1 to wk 60 of life in both types of tissues. Moreover, the expression of SH protein tyrosine phosphatase-2 (SHP2), a tyrosine phosphatase involved in insulin signal transduction and regulation of the insulin signal, decreased significantly with age progression, in both the forebrain cortex and the cerebellum of rats. Thus, elements involved in the insulin-signaling pathway are regulated at the expression and/or functional level in the CNS, and this regulation may play a role in insulin resistance in the brain.
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PMID:Effects of age on elements of insulin-signaling pathway in central nervous system of rats. 1195 67

Islet amyloid polypeptide (IAPP) and insulin are copackaged and cosecreted by pancreatic islet beta-cells. Non-insulin-dependent (type II) diabetes mellitus (NIDDM) is characterized by dysfunction and depletion of these beta-cells and also, in more than 90% of patients, amyloid plaques containing fibrillar IAPP. An aggregated but not necessarily fibrillar form of IAPP is toxic in cell culture, suggesting that prefibrillar oligomeric (protofibrillar) IAPP may be pathogenic. We report here that IAPP generates oligomeric species in vitro that are consumed as beta-sheet-rich fibrils grow. Protofibrillar IAPP, like protofibrillar alpha-synuclein, which is implicated in Parkinson's disease pathogenesis, permeabilizes synthetic vesicles by a pore-like mechanism. The formation of the IAPP amyloid pore is temporally correlated to the formation of early IAPP oligomers and its disappearance to the appearance of amyloid fibrils. Neither pores nor oligomers were formed by the nonfibrillogenic rat IAPP variant. The IAPP amyloid pore may be critical to the pathogenic mechanism of NIDDM, as other amyloid pores may be to Alzheimer's disease and Parkinson's disease.
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PMID:Protofibrillar islet amyloid polypeptide permeabilizes synthetic vesicles by a pore-like mechanism that may be relevant to type II diabetes. 1223 75

The article traces the development of research on the naturally occurring amino acid L-3,4-dihydroxyphenylalanine (L-dopa), from the first synthesis of its D,L racemate in 1911, and the isolation of its L-isomer from seedling of Vicia faba beans to the amino acid's successful application, from 1961 onward, as the most efficacious drug treatment of Parkinson's disease (PD). Upon its isolation from legumes in 1913, L-dopa was declared to be biologically inactive. However, two early pharmacological studies, published in 1927 and 1930 respectively, proved (in the rabbit) that D,L-dopa exerted significant effects on glucose metabolism (causing marked hyperglycemia) and on arterial blood pressure. Interest in L-dopa's biological activity increased considerably following the discovery, in 1938, of the enzyme L-dopa decarboxylase and the demonstration that in the animal and human body L-dopa was enzymatically converted to dopamine (DA), the first biologically active amine in the biosynthetic chain of tissue catecholamines. This prompted, in the 1940s, many studies, both in animals and in humans, especially concerned with the vasopressor potential of L-dopa/DA. In the 1950s, the focus of L-dopa research shifted to its potential for replenishing the experimentally depleted (by insulin or reserpine) peripheral and brain catecholamine stores and the concomitant restoration of normal function. During that period, of special interest were the observations that L-dopa reversed the reserpine-induced state of "tranquilisation" and that its decarboxylation product DA occurred in high amounts in animal and human brain, with a preferential localization in the basal ganglia. These observations set the stage for the beginning of DA studies in PD brain. In 1960, the severe brain DA deficit, confined to patients with PD was discovered, and a year later L-dopa's strong therapeutic effect in patients with PD was demonstrated. In 1967, the chronic high-dose oral L-dopa regimen was successfully introduced into clinical practice. Despite some initial doubts about L-dopa's mechanism of action in PD, it is now generally recognized that L-dopa use in PD is a classic example of a brain neurotransmitter replacement therapy. However, the DA replacement potential of L-dopa may not be its sole action of interest, as suggested by recent evidence that L-dopa may also have its own biological activity in the CNS, independent of DA.
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PMID:L-DOPA: from a biologically inactive amino acid to a successful therapeutic agent. 1237 20

The immunoprivileged environment of the testes was first described in the 1930s, and the Sertoli cell was later identified as the main cell type responsible for this phenomenon. Recent work has examined the possibility of recreating this immunoprivileged environment at heterotopic sites using isolated Sertoli cells. These studies have focused on protection of pancreatic islets and neuronal cells from immune destruction in the hopes of reversing type I diabetes and Parkinson's disease. The absence of a definitive marker for identifying Sertoli cells at the transplant site has been an obstacle to this research. The current study examines the presence of a nuclear transcription factor, Sox9, which is preferentially expressed in Sertoli cells. Syngeneic Lewis rat Sertoli cells were transplanted into the renal subcapsular space and a subcutaneous site in Lewis female rats and examined histologically 21 days later. In addition, porcine Sertoli cells were transplanted into the renal subcapsular space in female SCID mice. Control testes and the transplant sites were examined immunohistochemically using an antibody to Sox9. The results from the study demonstrate that Sox9 expression is restricted to the Sertoli cells of the neonatal rat and porcine testis, indicating high homology between species. In addition, Sox9 expression was also observed in the testicular-like tubules that formed in both syngeneic and xenogeneic heterotopic transplants in rats and SCID mice. The Sox9 expression was restricted to the regions where Sertoli cells would be found in the native testis. These results suggest that the Sox9 protein is a useful marker in identifying Sertoli cells in heterotopic transplants in a manner similar to insulin as a marker for pancreatic islets.
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PMID:Identification of a specific Sertoli cell marker, Sox9, for use in transplantation. 1242 37

Protein-tyrosine kinase (PTKase) and protein-tyrosine phosphatase (PTPase) regulate the intracellular signal transduction in various biological processes. PTPase often negatively regulates the intracellular protein-tyrosine phosphorylation. PTPases are considered to be involved in the etiology of diabetes mellitus and neural diseases, such as Alzheimer's disease and Parkinson's disease. Therefore, PTPase inhibitors should be useful tools to study the role of PTPases in these diseases and other biological phenomena, and they hopefully may be developed into chemotherapeutic agents. We first discovered a naturally occurring PTPase inhibitor, dephostatin, in 1993. Later, we developed stable and safe dephostatin analogues by a molecular design approach employing the concept of CH/pi interaction. We prepared Et-3,4-dephostatin as a stable analogue and found it to inhibit PTP-1B and SHPTP-1 PTPases selectively. Et-3,4-dephostatin increased the tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), with or without insulin, in differentiated 3T3-L1 mouse adipocytes. It also increased the phosphorylation and activation of Akt. The analogue also enhanced translocation of glucose transporter 4 (GLUT4) from the cytoplasm to the membrane and 2-deoxyglucose transport. It also showed an in vivo antidiabetic effect in terms of reducing the high blood glucose level in KK-Ay mice after oral administration. Since Et-3,4-dephostatin contains a nitrosamine moiety, we designed nitrosamine-free dephostatin analogues employing the concept of CH/pi interaction. Then, we synthesized methoxime- and hexyl-methoxime-3,4-dephostatin as nitrosamine-free analogues. These analogues also showed antidiabetic activity in vivo and illustrate the utility of the CH/pi interaction molecular design approach.
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PMID:Molecular design and biological activities of protein-tyrosine phosphatase inhibitors. 1280 96

The immunoprotective nature of the testis has led to numerous investigations for its ability to protect cellular grafts. Sertoli cells (SCs) are at least partially responsible for this immunoprotective environment and survive allogeneic and xenogeneic transplantation. The ability of SCs to survive transplantation leads to the possibility that they could be engineered to deliver therapeutic proteins. As a model to test this hypothesis, we examined the ability of SCs that produce green fluorescent protein (GFP) to survive transplantation and continue expressing GFP. SCs were isolated from transgenic mice engineered to express GFP and transplanted as aggregates under the kidney capsule of severe combined immunodeficient (SCID) and Balb/c mice. Using this paradigm, it was possible to compare the survival of transgenic SCs directly in both immunodeficient and immunocompetent recipients. Fluorescence microscopy of the kidney capsule and immunohistochemistry of the grafts for GFP and GATA-4 revealed the presence of GFP-expressing SCs under the kidney capsule of SCID and Balb/c mice at both 30 and 60 days post-transplantation. In contrast, islets transplanted to Balb/c mice were rejected. Thus, SCs survive transplantation and continue to express GFP raising the possibility that SCs can be engineered using transgenic technology to produce proteins, such as insulin, factor VIII, or dopamine for the treatment of diabetes, hemophilia or Parkinson's disease, respectively.
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PMID:Genetically engineered Sertoli cells are able to survive allogeneic transplantation. 1472 69

Insulin has functions in the brain and dysregulation of these functions may contribute to the expression of late-life neurodegenerative disease. We provide a brief summary of research on the influence of insulin on normal brain function. We then review evidence that perturbation of this role may contribute to the symptoms and pathogenesis of various neurodegenerative disorders, such as Alzheimer's disease, vascular dementia, Parkinson's disease, and Huntington's disease. We conclude by considering whether insulin dysregulation contributes to neurodegenerative disorders through disease-specific or general mechanisms.
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PMID:Insulin and neurodegenerative disease: shared and specific mechanisms. 1498 May 32

More than 20 syndromes among the significant and increasing number of degenerative diseases of neuronal tissues are known to be associated with diabetes mellitus, increased insulin resistance and obesity, disturbed insulin sensitivity, and excessive or impaired insulin secretion. This review briefly presents such syndromes, including Alzheimer disease, ataxia-telangiectasia, Down syndrome/trisomy 21, Friedreich ataxia, Huntington disease, several disorders of mitochondria, myotonic dystrophy, Parkinson disease, Prader-Willi syndrome, Werner syndrome, Wolfram syndrome, mitochondrial disorders affecting oxidative phosphorylation, and vitamin B(1) deficiency/inherited thiamine-responsive megaloblastic anemia syndrome as well as their respective relationship to malignancies, cancer, and aging and the nature of their inheritance (including triplet repeat expansions), genetic loci, and corresponding functional biochemistry. Discussed in further detail are disturbances of glucose metabolism including impaired glucose tolerance and both insulin-dependent and non-insulin-dependent diabetes caused by neurodegeneration in humans and mice, sometimes accompanied by degeneration of pancreatic beta-cells. Concordant mouse models obtained by targeted disruption (knock-out), knock-in, or transgenic overexpression of the respective transgene are also described. Preliminary conclusions suggest that many of the diabetogenic neurodegenerative disorders are related to alterations in oxidative phosphorylation (OXPHOS) and mitochondrial nutrient metabolism, which coincide with aberrant protein precipitation in the majority of affected individuals.
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PMID:Neurodegenerative disorders associated with diabetes mellitus. 1517 61

alpha-Synuclein is a pre-synaptic protein, the function of which is not completely understood, but its pathological form is involved in neurodegenerative diseases. In vitro, alpha-synuclein spontaneously forms amyloid fibrils. Here, we report that alphaB-crystallin, a molecular chaperone found in Lewy bodies that are characteristic of Parkinson's disease (PD), is a potent in vitro inhibitor of alpha-synuclein fibrillization, both of wild-type and the two mutant forms (A30P and A53T) that cause familial, early onset PD. In doing so, large irregular aggregates of alpha-synuclein and alphaB-crystallin are formed implying that alphaB-crystallin redirects alpha-synuclein from a fibril-formation pathway towards an amorphous aggregation pathway, thus reducing the amount of physiologically stable amyloid deposits in favor of easily degradable amorphous aggregates. alpha-Synuclein acts as a molecular chaperone to prevent the stress-induced, amorphous aggregation of target proteins. Compared to wild-type alpha-synuclein, both mutant forms have decreased chaperone activity in vitro against the aggregation of reduced insulin at 37 degrees C and the thermally induced aggregation of betaL-crystallin at 60 degrees C. Wild-type alpha-synuclein abrogates the chaperone activity of alphaB-crystallin to prevent the precipitation of reduced insulin. Interaction between these two chaperones and formation of a complex are also indicated by NMR spectroscopy, size-exclusion chromatography and mass spectrometry. In summary, alpha-synuclein and alphaB-crystallin interact readily with each other and affect each other's properties, in particular alpha-synuclein fibril formation and alphaB-crystallin chaperone action.
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PMID:Interaction of the molecular chaperone alphaB-crystallin with alpha-synuclein: effects on amyloid fibril formation and chaperone activity. 1523 75


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