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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two mutations in the gene encoding alpha-synuclein have been linked to early-onset Parkinson's disease (PD). alpha-Synuclein is a component of Lewy bodies, the fibrous cytoplasmic inclusions characteristic of nigral dopaminergic neurons in the PD brain. This connection between genetics and pathology suggests that the alpha-synuclein mutations may promote PD pathogenesis by accelerating Lewy body formation. To test this, we studied alpha-synuclein folding and aggregation in vitro, in the absence of other Lewy body-associated molecules. We demonstrate here that both mutant forms of alpha-synuclein (A53T and A30P) are, like wild-type alpha-synuclein (WT), disordered in dilute solution. However, at higher concentrations, Lewy body-like fibrils and discrete spherical assemblies are formed; most rapidly by A53T. Thus, mutation-induced acceleration of alpha-synuclein fibril formation may contribute to the early onset of familial PD.
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PMID:Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. 980 58

Parkinson's disease is the second most common age-related neurodegenerative disease, resulting from loss of dopaminergic neurons in the substantia nigra. The aggregation and fibrillation of alpha-synuclein has been implicated as a causative factor in the disease, and the process of fibril formation has been intensively studied in vitro with dilute protein solutions. However, the intracellular environment of proteins is crowded with other macromolecules, whose concentration can reach 400 g/l. To address this discrepancy, the effect of molecular crowding on alpha-synuclein fibrillation has being studied. The addition of high concentrations of different polymers (proteins, polysaccharides and polyethylene glycols) dramatically accelerated alpha-synuclein fibrillation in vitro. The magnitude of the accelerating effect depended on the nature of the polymer, its length and concentration. Our results suggest that the major factor responsible for the accelerated fibrillation under crowded conditions is the excluded volume.
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PMID:Accelerated alpha-synuclein fibrillation in crowded milieu. 1194 2

One of the most prevalent degenerative disorders of the nervous system is Parkinson's disease. The etiology of this disease is for the most part unknown, although it is posited to arise from an interaction of genetic and environmental factors. Although in vivo animal studies have been used to examine the effects of a number of Parkinson-inducing compounds, there is little information on reliable in vitro methodologies that can recapitulate the previously observed in vivo results. Here, we describe a method for generating mixed and chimeric neuron/glial cultures of postnatal substantia nigra (SN), independent of other monoaminergic nuclei in the ventral midbrain. Since many toxins do not affect regions of the midbrain except the SN, use of whole ventral midbrain from embryos can dilute any measurement of cell death. By specifically culturing ventrolateral midbrain containing the substantia nigra, one can more directly target the effects of dopaminergic toxins. In addition, this method can be used to test potential therapies for amelioration of Parkinson's disease.
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PMID:Method for culturing postnatal substantia nigra as an in vitro model of experimental Parkinson's disease. 1203 29

Protein misfolding and aberrant polymerization are salient features of virtually all central neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease, triplet repeat disorders, tauopathies, and prion diseases. In many instances, a single amino acid change can predispose to disease by increasing the production and/or changing the biophysical properties of a specific protein. Possible pathogenic similarities among the cerebral proteopathies suggest that therapeutic agents interfering with the proteopathic cascade might be effective against a wide range of diseases. However, testing compounds preclinically will require disease-relevant animal models. Numerous transgenic mouse models of beta-amyloidosis, tauopathy, and other aspects of AD have now been produced, but none of the existing models fully recapitulates the pathology of AD. In an attempt to more faithfully replicate the human disease, we infused dilute AD-brain extracts into Tg2576 mice at 3-months of age (i.e. 5-6 months prior to the usual onset of beta-amyloid deposition). We found that intracerebral infusion of AD brain extracts results in: 1). Premature deposition of beta-amyloid in eight month-old, beta-amyloid precursor protein ( betaAPP)-transgenic mice (Kane et al., 2000); 2). augmented amyloid load in the injected hemisphere of 15 month-old transgenic mice; 3). evidence for the spread of pathology to other brain areas, possibly by neuronal transport mechanisms; and 4). tau hyperphosphorylation (but not neurofibrillary pathology) in axons passing through the injection site. The seeding of beta-amyloid in vivo by AD brain extracts suggests pathogenic similarities between beta-amyloidoses such as AD and other cerebral proteopathies such as the prionoses, and could provide a new model for studying the proteopathic cascade and its neuronal consequences in neurodegenerative diseases.
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PMID:Modeling Alzheimer's disease and other proteopathies in vivo: is seeding the key? 1237 22

Diagnostic tests for Alzheimer's disease (AD) involving tropicamide blockade of cholinergic oculomotor functions were examined in AD patients (n=15), Parkinson's disease (PD) patients (n=15), and non-clinical control (NC) participants (n=15). Pupillographic methods were used to measure pupil diameter and pupillary light reflexes after double-blind ocular administration of dilute tropicamide (0.01%) in one eye and saline in the other eye. Changes in pupil size were measured in bright background light and near-darkness. Tropicamide increased pupil diameter to a similar extent in all three groups in light and darkness. Tropicamide also reduced the amplitude and latency of the pupillary light reflex to a similar extent for all three groups. Tropicamide pupillary response tests, therefore, were not sensitive or specific diagnostic tests for AD. Peak constriction amplitude of the pupillary light reflex was significantly reduced in both eyes in AD and PD groups relative to non-clinical controls, but AD and PD groups did not differ significantly. The pupillary light reflex test, therefore, was sensitive to AD, but lacked adequate specificity. Finally, peak constriction amplitude correlated significantly with dementia severity and donepezil treatment may have partially normalized pupillary light reflex abnormalities in AD patients. The pupillary light reflex test, therefore, may index central cholinergic dysfunction associated with disease progression and improvement in cholinergic function associated with pharmacologic treatment response in AD.
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PMID:Tropicamide effects on pupil size and pupillary light reflexes in Alzheimer's and Parkinson's disease. 1256 41

One promising therapy for the treatment of Parkinson's disease is transplantation of embryonic ventral mesencephalic tissue. Unfortunately, up to 95% of grafted cells die, many via apoptosis. In this study we attempted to prevent anoikis-induced cell death, which is triggered during the preparation of cells for grafting, and examine the impact on graft viability and function. We utilized the extracellular matrix molecule tenascin-C (tenascin) and an antibody (Ab) to the cell adhesion molecule L1 to specifically mimic survival signals induced by cell-matrix and cell-cell interactions. In vitro, both tenascin- and L1 Ab-treated cultures doubled the number of tyrosine hydroxylase immunoreactive (THir) neurons compared to control. Additionally, cell survival assays determined that tenascin and L1 Ab-treated cell suspensions yielded more metabolically active and fewer dead cells than control suspensions. In contrast to the culture results, tenascin- and L1 Ab-treated mesencephalic grafts did not yield an increase in the number of THir neurons using our standard grafting paradigm (3 microl of 100,000 cells/microl). However, under low-density conditions (3 microl of 3,000 cells/microl), tenascin augmented grafted THir neuron survival. These findings are consistent with the view that cell density can dramatically influence the degree of stress placed on THir neurons and consequently affect the success of survival strategies in vivo. In conclusion, pretreatment with tenascin may prove beneficial to prevent anoikis in dilute cell suspension grafts, while long-term in vivo delivery methods need to be explored to determine if L1 can prevent anoikis in grafts of mesencephalic dopamine neurons after transplantation.
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PMID:Interference with anoikis-induced cell death of dopamine neurons: implications for augmenting embryonic graft survival in a rat model of Parkinson's disease. 1289 10

The natively disordered protein alpha-synuclein is the primary component of Lewy bodies, the cellular hallmark of Parkinson's disease. Most studies of this protein are performed in dilute solution, but its biologically relevant role is performed in the crowded environment inside cells. We addressed the effects of macromolecular crowding on alpha-synuclein by combining NMR data acquired in living Escherichia coli with in vitro NMR data. The crowded environment in the E.coli periplasm prevents a conformational change that is detected at 35 degrees C in dilute solution. This change is associated with an increase in hydrodynamic radius and the formation of secondary structure in the N-terminal 100 amino acid residues. By preventing this temperature-induced conformational change, crowding in the E.coli periplasm stabilizes the disordered monomer. We obtain the same stabilization in vitro upon crowding alpha-synuclein with 300 g/l of bovine serum albumin, indicating that crowding alone is sufficient to stabilize the disordered, monomeric protein. Two disease-associated variants (A30P and A53T) behave in the same way in both dilute solution and in the E.coli periplasm. These data reveal the importance of approaching the effects of macromolecular crowding on a case-by-case basis. Additionally, our work shows that discrete structured protein conformations may not be achieved by alpha-synuclein inside cells, implicating the commonly overlooked aspect of macromolecular crowding as a possible factor in the etiology of Parkinson's disease.
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PMID:Macromolecular crowding in the Escherichia coli periplasm maintains alpha-synuclein disorder. 1634 31

Natively disordered proteins are a growing class of anomalies to the structure-function paradigm. The natively disordered protein alpha-synuclein is the primary component of Lewy bodies, the cellular hallmark of Parkinson's disease. We noticed a dramatic difference in dilute solution 1H-15N Heteronuclear Single Quantum Coherence (HSQC) spectra of wild-type alpha-synuclein and two disease-related mutants (A30P and A53T), with spectra collected at 35 degrees C showing fewer cross-peaks than spectra acquired at 10 degrees C. Here, we show the change to be the result of a reversible conformational exchange linked to an increase in hydrodynamic radius and secondary structure as the temperature is raised. Combined with analytical ultracentrifugation data showing alpha-synuclein to be monomeric at both temperatures, we conclude that the poor quality of the 1H-15N HSQC spectra obtained at 35 degrees C is due to conformational fluctuations that occur on the proton chemical shift time scale. Using a truncated variant of alpha-synuclein, we show the conformational exchange occurs in the first 100 amino acids of the protein. Our data illustrate a key difference between globular and natively disordered proteins. The properties of globular proteins change little with solution conditions until they denature cooperatively, but the properties of natively disordered proteins can vary dramatically with solution conditions.
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PMID:Temperature-induced reversible conformational change in the first 100 residues of alpha-synuclein. 1645 21

The dementia of Parkinson's disease (PD) and Alzheimer's disease (AD) share neurochemical and neuroanatomical characteristics. Pupillary supersensitivity to dilute pilocarpine and to the cholinergic antagonist tropicamide were described in AD, although the specificity has been debated. In the present work we examine whether a similar supersensitivity of the pupil exists in PD patients with and without dementia. PD patients (n = 36,13 demented) and 14 neurologically healthy age-matched controls were examined. The pupil size was determined at baseline and 30 min after the instillation of 0.01% tropicamide, and measured using the Goldmann perimeter. All 13 demented PD patients, but only eight of the 23 non-demented patients (35%), had a mydriatic response to dilute tropicamide. Among controls, only 2 14 (14%) had mydriaris (p < 0.001). This supersensitivity of the pupil of demented PD patients to a cholinergic antagonist may reflect either a reduced parasympathetic tone or an artifact of increased corneal permeability and decreased lacrimation and blinking. We conclude that the tropicamide eye drop test is not useful as a diagnostic tool for dementia in PD.
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PMID:The tropicamide eye drop test in Parkinson's disease. 1859 Oct 79

Certain metals lead to increased risk of Parkinson's disease (PD) and the aggregation of alpha-synuclein is implicated in the PD pathology. Although alpha-synuclein fibrillation has been extensively studied in dilute solutions in vitro, the intracellular environment is highly crowded. We are showing here that certain metals cause a significant acceleration of alpha-synuclein fibrillation in the presence of high concentrations of various macromolecules mostly through decreasing the fibrillation lagtime. The faster fibrillation in crowded environments in the presence of heavy metals suggests a simple molecular basis for the observed elevated risk of PD due to exposure to metals.
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PMID:Concerted action of metals and macromolecular crowding on the fibrillation of alpha-synuclein. 1907 19


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