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)

Alzheimer's disease (AD) is a progressive neurodegenerative disease for which there are few therapeutic regimens that influence the underlying pathogenic phenotypes. However, of the currently available therapies, exercise training is considered to be one of the best candidates for amelioration of the pathological phenotypes of AD. Therefore, we directly investigated exercise training to determine whether it was able to ameliorate the molecular pathogenic phenotypes in the brain using a neuron-specific enolase (NSE)/Swedish mutation of amyloid precursor protein (APPsw) transgenic (Tg) mice as a novel AD model. To accomplish this, Non-Tg and NSE/ APPsw Tg mice were subjected to exercise on a treadmill for 16 weeks, after which their brains were evaluated to determine whether any changes in the pathological phenotype-related factors had occurred. The results indicated (i) that amyloid beta-42 (Abeta-42) peptides were significantly decreased in the NSE/APPsw Tg mice following exercise training; (ii) that exercise training inhibited the apoptotic biochemical cascades, including cytochrome c, caspase-9, caspase-3 and Bax; (iii) that the glucose transporter-1 (GLUT-1) and brain-derived neurotrophic factor (BDNF) proteins induced by exercise training protected the neurons from injury by inducing the concomitant expression of genes that encode proteins such as superoxide dismutase-1 (SOD-1), catalase and Bcl-2, which suppress oxidative stress and excitotoxic injury; (iv) that heat-shock protein-70 (HSP-70) and glucose-regulated protein-78 (GRP-78) were significantly increased in the exercise (EXE) group when compared to the sedentary (SED) group, and that these proteins may benefit the brain by making it more resistant to stress-induced neuron cell damage; (v) and that exercise training contributed to the restoration of normal levels of serum total cholesterol, insulin and glucose. Taken together, these results suggest that exercise training represents a practical therapeutic strategy for human subjects suffering from AD. Moreover, this training has the potential for use in new therapeutic strategies for the treatment of other chronic disease including diabetes, cardiovascular and Parkinson's disease.
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PMID:Exercise training acts as a therapeutic strategy for reduction of the pathogenic phenotypes for Alzheimer's disease in an NSE/APPsw-transgenic model. 1881 61

The heat shock protein Hsp104 has been reported to possess the ability to modulate protein aggregation and toxicity and to "catalyze" the disaggregation and recovery of protein aggregates, including amyloid fibrils, in yeast, Escherichia coli, mammalian cell cultures, and animal models of Huntington's disease and Parkinson's disease. To provide mechanistic insight into the molecular mechanisms by which Hsp104 modulates aggregation and fibrillogenesis, the effect of Hsp104 on the fibrillogenesis of amyloid beta (Abeta) was investigated by characterizing its ability to interfere with oligomerization and fibrillogenesis of different species along the amyloid-formation pathway of Abeta. To probe the disaggregation activity of Hsp104, its ability to dissociate preformed protofibrillar and fibrillar aggregates of Abeta was assessed in the presence and in the absence of ATP. Our results show that Hsp104 inhibits the fibrillization of monomeric and protofibrillar forms of Abeta in a concentration-dependent but ATP-independent manner. Inhibition of Abeta fibrillization by Hsp104 is observable up to Hsp104/Abeta stoichiometric ratios of 1:1000, suggesting a preferential interaction of Hsp104 with aggregation intermediates (e.g., oligomers, protofibrils, small fibrils) on the pathway of Abeta amyloid formation. This hypothesis is consistent with our observations that Hsp104 (i) interacts with Abeta protofibrils, (ii) inhibits conversion of protofibrils into amyloid fibrils, (iii) arrests fibril elongation and reassembly, and (iv) abolishes the capacity of protofibrils and sonicated fibrils to seed the fibrillization of monomeric Abeta. Together, these findings suggest that the strong inhibition of Abeta fibrillization by Hsp104 is mediated by its ability to act at different stages and target multiple intermediates on the pathway to amyloid formation.
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PMID:Hsp104 targets multiple intermediates on the amyloid pathway and suppresses the seeding capacity of Abeta fibrils and protofibrils. 1885 77

Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs) in in vitro models of Alzheimer and Parkinson disease. Primary cultures of hippocampal and ventral mesencephalic neurons were treated for 24 h with amyloid beta (Abeta(1-42)) peptide 1-42 and 6-OHDA, respectively. DPCs isolated from adult rat incisors were previously cultured in tissue culture inserts and added to the neuron cultures 2 days prior to neurotoxin treatment. Cell viability was assessed by the MTT assay. The co-culture with DPCs significantly attenuated 6-OHDA and Abeta(1-42)-induced toxicity in primary cultures of mesencephalic and hippocampal neurons, and lead to an increase in neuronal viability in untreated cultures, suggesting a neurotrophic effect in both models. Furthermore, human dental pulp cells expressed a neuronal phenotype and produced the neurotrophic factors NGF, GDNF, BDNF, and BMP2 shown by microarray screening and antibody staining for the representative proteins. DPCs protected primary neurons in in vitro models of Alzheimer's and Parkinson's disease and can be viewed as possible candidates for studies on cell-based therapy.
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PMID:The neuroprotective effect of dental pulp cells in models of Alzheimer's and Parkinson's disease. 1897 63

Using a method based on ESR spectroscopy and spin-trapping, we have shown that Abeta (amyloid beta-peptide) (implicated in Alzheimer's disease), alpha-synuclein (implicated in Parkinson's disease), ABri (British dementia peptide) (responsible for familial British dementia), certain toxic fragments of the prion protein (implicated in the transmissible spongiform encephalopathies) and the amylin peptide (found in the pancreas in Type 2 diabetes mellitus) all have the common ability to generate H(2)O(2) in vitro. Numerous controls (reverse, scrambled and non-toxic peptides) lacked this property. We have also noted a positive correlation between the ability of the various proteins tested to generate H(2)O(2) and their toxic effects on cultured cells. In the case of Abeta and ABri, we have shown that H(2)O(2) is generated as a short burst during the early stages of aggregation and is associated with the presence of protofibrils or oligomers, rather than mature fibrils. H(2)O(2) is readily converted into the aggressive hydroxyl radical by Fenton chemistry, and this extremely reactive radical could be responsible for much of the oxidative damage seen in all of the above disorders. We suggest that the formation of a redox-active complex involving the relevant amyloidogenic protein and certain transition-metal ions could play an important role in the pathogenesis of several different protein misfolding disorders.
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PMID:Metal-dependent generation of reactive oxygen species from amyloid proteins implicated in neurodegenerative disease. 1902 43

The prevalence of cerebral amyloid angiopathy (CAA) and its association with intellectual decline in idiopathic Parkinson's disease (iPD) remain unclear. To identify the role of CAA in iPD dementia the prevalence and severity of CAA were investigated, with particular respect to changes in vessel wall structure. Twenty-eight autopsy Parkinsonian brains and fourteen age-matched controls, post-mortem revised histopathologically for the presence of alpha-synuclein and Alzheimer's disease (AD)-type pathology, using standardized clinico-neuropathological criteria, underwent further investigation. Histological, immunohistochemical staining methods with antibodies to amyloid beta-peptide, alpha-actin, collagen III, collagen IV and CD34 as well as ultrastructural methods were used. The findings showed that the prevalence of CAA in the iPD cohort was higher (53%) than in controls (28%). CAA occurred more frequently in the iPD+AD (70%) sub-set than in the iPD-AD (44%) one. The progression of CAA was differentiated, with predominance of mild stage. Diminished smooth muscle actin and collagen IV expression in the vascular media with concomitant collagen III positive immunoreactivity in the intima were observed only in very severe CAA. Ultrastructural assay revealed degenerative changes in vessel smooth muscle cells and thickening of their basement membrane with the focal accumulation of amyloid fibres and fibrillar collagen in both iPD -AD and iPD+AD cases, but the most severe CAA-type changes were visible in the iPD+AD sub-set. The same type of immunoreactivity (Abeta42 positive and Abeta40 positive) of arterial CAA and parenchymal neuritic plaques, as well as capillary CAA and diffuse plaques (Abeta42 positive and Abeta40 negative), may indicate pathogenic similarities and differences between both types of degenerative changes on the one hand and time-different changes or local different processing of amyloid precursor protein on the other.
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PMID:Amyloid angiopathy in idiopathic Parkinson's disease. Immunohistochemical and ultrastructural study. 1916 67

Temporins constitute a family of amphipathic alpha-helical antimicrobial peptides (AMP) and contain some of the shortest cytotoxic peptides, comprised of only 10-14 residues. General characteristics of temporins parallel those of other AMP, both in terms of structural features and biophysical properties relating to their interactions with membrane lipids, with selective lipid-binding properties believed to underlie the discrimination between target vs host cells. Lipid-binding properties also contribute to the cytotoxicity AMP, causing permeabilization of their target cell membranes. The latter functional property of AMP involves highly interdependent acidic phospholipid-induced conformational changes, aggregation, and formation of toxic oligomers in the membrane. These oligomers are subsequently converted to amyloid-type fibers, as demonstrated for e.g. temporins B and L in our laboratory, and more recently for dermaseptins by Auvynet et al. Amyloid state represents the generic minimum in the folding/aggregation free energy landscape, and for AMP its formation most likely serves to detoxify the peptides, in keeping with the current consensus on mature amyloid being inert and non-toxic. The above scenario is supported by sequence analyses of temporins as well as other amphipathic alpha-helical AMP belonging to diverse families. Accordingly, sequence comparison identifies 'conformational switches', domains with equal probabilities for adopting random coil, alpha-helical and beta-sheet structures. These regions were further predicted also to aggregate and assemble into amyloid beta-sheets. Taken together, the lipid-binding properties and structural characterization lend support to the notion that the mechanism of membrane permeabilization by temporins B and L and perhaps of most AMP could be very similar, if not identical, to that of the paradigm amyloid forming cytotoxic peptides, responsible for degenerative cell loss in e.g. prion, Alzheimer's and Parkinson's disease, and type 2 diabetes.
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PMID:Binding of amphipathic alpha-helical antimicrobial peptides to lipid membranes: lessons from temporins B and L. 1939 5

alpha-Synuclein is an intrinsically disordered protein that appears in aggregated forms in the brains of patients with Parkinson's disease. The conversion from monomer to aggregate is complex, and aggregation rates are sensitive to changes in amino acid sequence and environmental conditions. It has previously been observed that alpha-synuclein aggregates faster at low pH than at neutral pH. Here, we combine NMR spectroscopy and molecular simulations to characterize alpha-synuclein conformational ensembles at both neutral and low pH in order to understand how the altered charge distribution at low pH changes the structural properties of these ensembles and leads to an increase in aggregation rate. The N-terminus, which has a small positive charge at neutral pH due to a balance of positively and negatively charged amino acid residues, is very positively charged at low pH. Conversely, the acidic C-terminus is highly negatively charged at neutral pH and becomes essentially neutral and hydrophobic at low pH. Our NMR experiments and replica exchange molecular dynamics simulations indicate that there is a significant structural reorganization within the low-pH ensemble relative to that at neutral pH in terms of long-range contacts, hydrodynamic radius, and the amount of heterogeneity within the conformational ensembles. At neutral pH, there is a very heterogeneous ensemble with transient contacts between the N-terminus and the non-amyloid beta component (NAC); however, at low pH, there is a more homogeneous ensemble that exhibits strong contacts between the NAC and the C-terminus. At both pH values, transient contacts between the N- and C-termini are observed, the NAC region shows similar exposure to solvent, and the entire protein shows similar propensities to secondary structure. Based on the comparison of the neutral- and low-pH conformational ensembles, we propose that exposure of the NAC region to solvent and the secondary-structure propensity are not factors that account for differences in propensity to aggregate in this context. Instead, the comparison of the neutral- and low-pH ensembles suggests that the change in long-range interactions between the low- and neutral-pH ensembles, the compaction of the C-terminal region at low pH, and the uneven distribution of charges across the sequence are key to faster aggregation.
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PMID:Structural reorganization of alpha-synuclein at low pH observed by NMR and REMD simulations. 1957 20

The aggregation of numerous peptides or proteins has been linked to the onset of disease, including Abeta (amyloid beta-peptide) in AD (Alzheimer's disease), asyn (alpha-synuclein) in Parkinson's disease and amylin in Type 2 diabetes. Diverse amyloidogenic proteins can often be cut down to an SRE (self-recognition element) of as few as five residues that retains the ability to aggregate. SREs can be used as a starting point for aggregation inhibitors. In particular, N-methylated SREs can bind to a target on one side, but have hydrogen-bonding blocked on their methylated face, interfering with further assembly. We applied this strategy to develop Abeta toxicity inhibitors. Our compounds, and a range of compounds from the literature, were compared under the same conditions, using biophysical and toxicity assays. Two N-methylated D-peptide inhibitors with unnatural side chains were the most effective and can reverse Abeta-induced inhibition of LTP (long-term potentiation) at concentrations as low as 10 nM. An SRE in asyn (VAQKTV) was identified using solid-state NMR. When VAQKTV was N-methylated, it was able to disrupt asyn aggregation. N-methylated derivatives of the SRE of amylin are also able to inhibit amylin aggregation.
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PMID:Inhibitors of protein aggregation and toxicity. 1961 77

Transthyretin (TTR) is a plasma protein mostly known for being the transporter of thyroxine and retinol. When mutated, TTR is also well-described as the cause of familial amyloid polyneuropathy, a neurodegenerative lethal disorder characterized by systemic deposition of TTR amyloid fibrils, particularly in the peripheral nervous system. Recent studies have determined that besides its carrier properties, TTR is an important protein in peripheral and central nervous system physiology, namely by participating in behavior, in the maintenance of normal cognitive processes during ageing, amidated neuropeptide processing and nerve regeneration. Additionally, it has been proposed that TTR is neuroprotective in Alzheimer's disease, by preventing the formation of amyloid beta fibrils. With the advent of powerful screening techniques, TTR has also been linked to a number of other pathological conditions, including Parkinson's disease, schizophrenia, depression, among others. These associations, together with the recently unraveled nervous system-related functions, suggest that the relevance of TTR in physiology, particularly in neurobiology, is undervalued and that additional research in this field is needed. The aim of this review is to integrate in a critical perspective the current scattered knowledge concerning TTR most and less acknowledged functions and its association with several neuropathologies.
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PMID:Transthyretin: more than meets the eye. 1966 14

Some neurodegenerative diseases such as Alzheimer disease (AD) and Parkinson disease are caused by protein misfolding. In AD, amyloid beta-peptide (Abeta) is thought to be a toxic agent by self-assembling into a variety of aggregates involving soluble oligomeric intermediates and amyloid fibrils. Here, we have designed several green fluorescent protein (GFP) variants that contain pseudo-Abeta beta-sheet surfaces and evaluated their abilities to bind to Abeta and inhibit Abeta oligomerization. Two GFP variants P13H and AP93Q bound tightly to Abeta, K(d) = 260 nM and K(d) = 420 nM, respectively. Moreover, P13H and AP93Q were capable of efficiently suppressing the generation of toxic Abeta oligomers as shown by a cell viability assay. By combining the P13H and AP93Q mutations, a super variant SFAB4 comprising four strands of Abeta-derived sequences was designed and bound more tightly to Abeta (K(d) = 100 nM) than those having only two pseudo-Abeta strands. The SFAB4 protein preferentially recognized the soluble oligomeric intermediates of Abeta more than both unstructured monomer and mature amyloid fibrils. Thus, the design strategy for embedding pseudo-Abeta beta-sheet structures onto a protein surface arranged in the beta-barrel structure is useful to construct molecules capable of binding tightly to Abeta and inhibiting its aggregation. This strategy may provide implication for the diagnostic and therapeutic development in the treatment of AD.
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PMID:Rational design of amyloid beta peptide-binding proteins: pseudo-Abeta beta-sheet surface presented in green fluorescent protein binds tightly and preferentially to structured Abeta. 1973 70


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