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)

Alpha-synuclein modulates dopamine homeostasis in dopamine-producing neurons of substantia nigra, partly through regulation of human dopamine transporter (hDAT) activity. To identify the underlying mechanisms, we disrupted the modulation of hDAT activity by wild-type (wt) alpha-synuclein, and its familial Parkinson's disease linked mutants A30P and A53T, by mild trypsinization (0.1%, 30 s) of Ltk(-) cotransfected cells. Trypsin completely reversed the attenuation of hDAT function mediated by wt and the A30P mutant. In A53T coexpressing cells, where DAT activity is not downregulated, trypsinization did not induce any changes. These effects of trypsin were mimicked by collagenase I and Dispase (0.1%, 1 min each) but not by chymotrypsin, Pronase, or papain (0.1%, up to 2 min each). Trypsin increased dopamine uptake in rat primary mesencephalic neurons, suggesting that DAT activity is also subjected to modulation by alpha-synuclein in these neurons that endogenously coexpress both proteins. In trypsinized cells, dopamine accelerated both production of reactive oxygen species and cell death in hDAT and wt or A30P, but not A53T, coexpressing cells, compared to nontrypsinized cells. Paradoxically, trypsin increased the protein-protein interactions between the synuclein variants and hDAT, without any noticeable proteolysis of these proteins. hDAT-alpha-synuclein protein-protein interactions occurred through residues 58-107 (NAC domain) of the alpha-synuclein variants and residues 598-620 of the carboxy-terminal tail of hDAT, in both trypsinized and nontrypsinized cells. Confocal microscopy and biotinylation studies show that, in cells expressing the wt or A30P variants, but not the A53T mutant, hDAT is sequestered away from the plasma membrane into the cytoplasm, an effect that is reversed by trypsin. These results show that alpha-synuclein modulates hDAT function through trafficking of the transporter in a process that can be disrupted by trypsin.
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PMID:Trypsin disrupts the trafficking of the human dopamine transporter by alpha-synuclein and its A30P mutant. 1475 60

Alzheimer's disease (AD), the most common type of dementia, and Parkinson's disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on "special" isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of "gene hunting" have evolved during the last few years and the significance of finding genes such as the presenilins, alpha- synuclein, parkin and DJ- 1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links.
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PMID:Chasing genes in Alzheimer's and Parkinson's disease. 1499 61

Recent studies have shown that the neurodegenerative process in disorders with Lewy body formation, such as Parkinson's disease and dementia with Lewy bodies, is associated with alpha-synuclein accumulation and that beta-synuclein might protect the central nervous system from the neurotoxic effects of alpha-synuclein. However, the mechanisms are unclear. The main objective of the present study was to investigate the potential involvement of the serine threonine kinase Akt (also known as protein kinase B) signaling pathway in the mechanisms of beta-synuclein neuroprotection. For this purpose, Akt activity and cell survival were analyzed in synuclein-transfected B103 neuroblastoma cells and primary cortical neurons. Beta-synuclein transfection resulted in increased Akt activity and conferred protection from the neurotoxic effects of rotenone. Down-regulation of Akt expression resulted in an increased susceptibility to rotenone toxicity, whereas transfection with a lentiviral vector encoding for beta-synuclein was protective. The effects of beta-synuclein on the Akt pathway appear to be by direct interaction between these molecules and were independent of upstream signaling molecules. Taken together, these results indicate that the mechanisms of beta-synuclein neuroprotection might involve direct interactions between beta-synuclein and Akt and suggest that this signaling pathway could be a potential therapeutic target for neurological conditions associated with parkinsonism and alpha-synuclein aggregation.
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PMID:Beta-synuclein regulates Akt activity in neuronal cells. A possible mechanism for neuroprotection in Parkinson's disease. 1502 13

The presynaptic protein alpha-synuclein has been implicated in both neuronal plasticity and neurodegenerative disease, but its normal function remains unclear. We described the induction of an amphipathic alpha-helix at the N terminus (exons 2-4) of alpha-synuclein upon exposure to phospholipid vesicles, and hypothesized that lipid-binding might serve as a functional switch by stabilizing alpha-synuclein in an active (alpha-helical) conformation. Others have shown that alpha and beta-synucleins inhibit phospholipase D (PLD), an enzyme involved in lipid-mediated signaling cascades and vesicle trafficking. Here, we report that all three naturally occurring synuclein isoforms (alpha, beta, and gamma-synuclein) are similarly effective inhibitors of PLD2 in vitro, as is the Parkinson's disease-associated mutant A30P. The PD-associated mutant A53T, however, is a more potent inhibitor of PLD2 than is wild-type alpha-synuclein. We analyze mutations of the alpha-synuclein protein to identify critical determinants of human PLD2 inhibition in vitro. Deletion of residues 56-102 (exon 4) decreases PLD2 inhibition significantly; this activity of exon 4 may require adoption of an alpha-helical conformation, as mutations that disrupt alpha-helicity also abrogate inhibition. Deletion of C-terminal residues 130-140 (exon 6) completely abolishes inhibitory activity. In addition, PLD2 inhibition is blocked by phosphorylation at serine 129 or at tyrosine residues 125 and 136, or by mutations that mimic phosphorylation at these sites. We conclude that PLD2 inhibition by alpha-synuclein is mediated by a lipid-stabilized alpha-helical structure in exon 4 and also by residues within exon 6, and that this inhibition can be modulated by phosphorylation of specific residues in exons 5 and 6.
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PMID:Structural determinants of PLD2 inhibition by alpha-synuclein. 1503 66

Synucleins are a family of small, highly charged proteins expressed predominantly in neurons. Since their discovery and characterization during the last decade, much has been learned about their structure, potential functions, interactions with other proteins, and roles in disease. One of these proteins, alpha-synuclein (alpha-syn), is the major building block of pathological inclusions that characterize many neurodegenerative disorders, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and neurodegeneration with brain iron accumulation type 1 (NBIA-1), which collectively are termed synucleinopathies. Furthermore, genetic and biological studies support a role for alpha-syn in the pathophysiology of these diseases. Therefore, research must be continued in order to better understand the functions of the synuclein proteins under normal physiological conditions as well as their role in diseases.
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PMID:Alpha-synuclein: normal function and role in neurodegenerative diseases. 1509 95

Accumulation of ubiquitinated proteins in inclusions is common to various neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, although it occurs in selective neurons in each disease. The mechanisms generating such abnormal aggregates and their role in neurodegeneration remain unclear. Inclusions appear in familial and non-familial cases of neurodegenerative disorders, suggesting that factors other than particular mutations contribute to protein accumulation and aggregation. Proteasome impairment triggered by aging or conditions such as oxidative stress may contribute to protein accumulation and aggregation in neurodegeneration. To test this hypothesis in mouse neuronal cells, we overexpressed a 20S proteasome beta5 subunit with an active site mutation. The N-terminal threonine to alanine substitution resulted in impairment of the chymotrypsin-like activity, which is a rate-limiting step in protein degradation by the proteasome. The Thr1Ala mutation was not lethal under homeostatic conditions. However, this single amino acid substitution significantly hypersensitized the cells to oxidative stress, triggering not only the accumulation and aggregation of ubiquitinated proteins, including synuclein, but also cell death. Our results demonstrate that this genetic manipulation of proteasome activity involving a single amino acid substitution causes the formation of protein aggregates in stressed neuronal cells independently of the occurrence of mutations in other cellular proteins. These results support the notion that proteasome disruption may be central to the development of familial as well as sporadic cases of neurodegeneration.
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PMID:A single amino acid substitution in a proteasome subunit triggers aggregation of ubiquitinated proteins in stressed neuronal cells. 1519 63

To better understand the pathogenesis of brain dysfunction in Gaucher disease (GD), we studied brain pathology in seven subjects with type 1 GD (four also exhibited parkinsonism and dementia), three with type 2 GD and four with type 3 GD. Unique pathologic patterns of disease involving the hippocampal CA2-4 regions and layer 4b of the calcarine cortex were identified. While these findings were common to all three GD phenotypes, the extent of the changes varied depending on the severity of disease. Cerebral cortical layers 3 and 5, hippocampal CA2-4, and layer 4b were involved in all GD patients. Neuronal loss predominated in both type 2 and type 3 patients with progressive myoclonic encephalopathy, whereas patients classified as type 1 GD had only astrogliosis. Adjacent regions and lamina, including hippocampal CA1 and calcarine lamina 4a and 4c were spared of pathology, highlighting the specificity of the vulnerability of selective neurons. Elevated glucocerebrosidase expression by immunohistochemistry was found in CA2-4. Hippocampal (45)Ca(2+) uptake autoradiography in rat brain was performed demonstrating that hippocampal CA2-4 neurons, rather than CA1 neurons, were calcium-induced calcium release sensitive (CICR-sensitive). These findings match recent biochemical studies linking elevated glucosylceramide levels to sensitization of CA2-4 RyaR receptors and 300% potentiation of neuronal CICR sensitivity. In two patients with type 1 GD and parkinsonism, numerous synuclein positive inclusions, similar to brainstem-type Lewy bodies found in Parkinson disease, were also found hippocampal CA2-4 neurons. These findings argue for a common cytotoxic mechanism linking aberrant glucocerebrosidase activity, neuronal cytotoxicity, and cytotoxic Lewy body formation in GD.
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PMID:Neuropathology provides clues to the pathophysiology of Gaucher disease. 1523 32

Pharmacological treatment of Parkinson's disease (PD) is entering a new and exciting era. Real promise now exists for the clinical application of a large range of molecules in development that will combat different aspects and stages of the condition. These include methyl- and ethyl-esterified forms of L-dopa (etilevodopa and melevodopa), inhibitors of enzymes such as monoamine oxidase type-B (eg, rasagiline), catechol-O-methyl transferase (eg, BIA-3202) and the monoamine re-uptake mechanism (eg, brasofensine). In addition, a range of full and partial dopamine agonists (eg, sumanirole, piribedil and BP-897) and their new formulations, for example, patch delivery systems (eg, rotigotine) are being developed. We also highlight non-dopaminergic treatments that will have wide ranging applications in the treatment of PD and L-dopa-induced dyskinesia. These include alpha2 adrenergic receptor antagonists (eg, fipamezole), adenosine A2A receptor antagonists (eg, istradefylline), AMPA receptor antagonists (eg, talampanel), neuronal synchronization modulators (eg, levetiracetam) and agents that interact with serotonergic systems such as 5-hydroxytryptamine (5-HT)1A agonists (eg, sarizotan) and 5-HT2A antagonists (eg, quetiapine). Lastly, we examine a growing number of neuroprotective agents that seek to halt or even reverse disease progression. These include anti-apoptotic kinase inhibitors (eg, CEP-1347), modulators of mitochondrial function (eg, creatine), growth factors (eg, leteprinim), neuroimmunophilins (eg, V-10367), estrogens (eg, MITO-4509), c-synuclein oligomerization inhibitors (eg, PAN-408) and sonic hedgehog ligands.
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PMID:Drugs in development for Parkinson's disease. 1529 67

The synuclein family includes three isoforms, termed alpha, beta and gamma. alpha-Synuclein accumulates in various pathological lesions resulting from neurodegenerative disorders including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy. However, neither beta- nor gamma-synuclein has been detected in Lewy bodies, and thus it is unclear whether these isoforms contribute to neurological pathology. In the present study, we used immunohistochemistry to demonstrate accelerated accumulation of beta- and gamma-synucleins in axonal spheroids in gracile axonal dystrophy (gad) mice, which do not express ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1). gamma-Synuclein immunoreactivity in the spheroids appeared in the gracile nucleus at 3 weeks of age and was maintained until 32 weeks. beta-Synuclein immunoreactivity appeared in spheroids around 12 weeks of age. In contrast, alpha-synuclein immunoreactivity was barely detectable in spheroids. Immunoreactivity for synaptophysin and ubiquitin were either faint or undetectable in spheroids. Given that UCH-L1 deficiency results in axonal degeneration and spheroid formation, our findings suggest that beta- and gamma-synuclein participate in the pathogenesis of axonal swelling in gad mice.
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PMID:Accumulation of beta- and gamma-synucleins in the ubiquitin carboxyl-terminal hydrolase L1-deficient gad mouse. 1530 32

Intraneuronal deposition containing alpha-synuclein is implicated in the pathogenesis of synuclein-opathies including Parkinsons disease (PD). Although it has been demonstrated that cytoplasmic inclusions of wild type alpha-synuclein are observed in the brain of PD patients and that alpha-synuclein mutations such as A30P and A53T accelerate aggregate formation, the exact mechanism by which alpha-synuclein forms insoluble aggregates is still controversial. In the present study, to understand the possible involvement of tissue transglutaminase (tTG) in aggregate formation of alpha-synuclein, SH-SY5Y cell lines stably expressing wild type or mutant (A30P or A53T) alpha-synuclein were created and aggregate formation of alpha-synuclein was observed upon activation of tTG. The data demonstrated that alpha-synuclein negligibly interacted with tTG and that activation of tTG did not result in the aggregate formation of alpha-synuclein in SH-SY5Y cells overexpressing either wild type or mutant alpha-synuclein. In addition, alpha-synuclein was not modified by activated tTG in situ. These data suggest that tTG is unlikely to be a contributing factor to the formation of aggregates of alpha-synuclein in a stable cell model.
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PMID:Tissue transglutaminase is not involved in the aggregate formation of stably expressed alpha-synuclein in SH-SY5Y human neuroblastoma cells. 1546 Apr 47


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