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)

Misfolded proteins accumulate in many neurodegenerative diseases, including huntingtin in Huntington's disease and alpha-synuclein in Parkinson's disease. The disease-causing proteins can take various conformations and are prone to aggregate and form larger cytoplasmic or nuclear inclusions. One approach to the development of therapeutic intervention for these diseases has been to identify chemical compounds that reduce the size or number of inclusions. We have, however, identified a compound that promotes inclusion formation in cellular models of both Huntington's disease and Parkinson's disease. Of particular interest, this compound prevents huntingtin-mediated proteasome dysfunction and reduces alpha-synuclein-mediated toxicity. These results demonstrate that compounds that increase inclusion formation may actually lessen cellular pathology in both Huntington's and Parkinson's diseases, suggesting a therapeutic approach for neurodegenerative diseases caused by protein misfolding.
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PMID:Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases. 1653 16

There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10 (CoQ10). We have reported that CoQ10 is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ10 slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ10 from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ10 significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ10 resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ10 and CoQ9 were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ10 elevated CoQ10 plasma levels and significantly increased brain levels of CoQ9, CoQ10, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ10 exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ10 in HD patients are warranted.
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PMID:Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice. 1664 50

Many late-onset neurodegenerative diseases, including Parkinson's disease, tauopathies, Huntington's disease and forms of spinocerebellar ataxia, are caused by aggregate-prone proteins. Previously we showed that mutant huntingtin is an autophagy substrate and that autophagy induction reduced soluble and aggregated huntingtin levels and attenuated its toxicity in cell, fly and mouse models of disease. We have recently shown in cell and fly models that autophagy induction may have general protective effects across a range of diseases caused by aggregate-prone intracellular proteins. First, we showed that this strategy reduces the levels of the primary toxin, the aggregate-prone mutant protein. Second, our recent work suggests that autophagy induction may have additional cytoprotective effects by protecting cells against a range of subsequent pro-apoptotic insults.
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PMID:Protective roles for induction of autophagy in multiple proteinopathies. 1687 96

We recently showed that lithium induces autophagy via inositol monophosphatase (IMPase) inhibition, leading to free inositol depletion and reduced myo-inositol-1,4, 5-triphosphate (IP3) levels. This represents a novel way of regulating mammalian autophagy, independent of the mammalian target of rapamycin (mTOR). Induction of autophagy by lithium led to enhanced clearance of autophagy substrates, like mutant huntingtin fragments and mutant alpha-synucleins, associated with Huntington's disease (HD) and some autosomal dominant forms of Parkinson's disease (PD), respectively. Similar effects were observed with a specific IMPase inhibitor and mood-stabilizing drugs that decrease inositol levels. This may represent a new therapeutic strategy for upregulating autophagy in the treatment of neurodegenerative disorders, where the mutant protein is an autophagy substrate. In this Addendum, we review these findings, and some of the speculative possibilities they raise.
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PMID:Inositol and IP3 levels regulate autophagy: biology and therapeutic speculations. 1687 97

Macroautophagy (henceforth referred to simply as autophagy) is a bulk degradation process involved in the clearance of long-lived proteins, protein complexes and organelles. A portion of the cytosol, with its contents to be degraded, is enclosed by double-membrane structures called autophagosomes/autophagic vacuoles, which ultimately fuse with lysosomes where their contents are degraded. In this review, we will describe how induction of autophagy is protective against toxic intracytosolic aggregate-prone proteins that cause a range of neurodegenerative diseases. Autophagy is a key clearance pathway involved in the removal of such proteins, including mutant huntingtin (that causes Huntington's disease), mutant ataxin-3 (that causes spinocerebellar ataxia type 3), forms of tau that cause tauopathies, and forms of alpha-synuclein that cause familial Parkinson's disease. Induction of autophagy enhances the clearance of both soluble and aggregated forms of such proteins, and protects against toxicity of a range of these mutations in cell and animal models. Interestingly, the aggregates formed by mutant huntingtin sequester and inactivate the mammalian target of rapamycin (mTOR), a key negative regulator of autophagy. This results in induction of autophagy in cells with these aggregates.
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PMID:Role of autophagy in the clearance of mutant huntingtin: a step towards therapy? 1697 7

Intracellular protein misfolding/aggregation are features of many late-onset neurodegenerative diseases, called proteinopathies. These include Alzheimer's disease, Parkinson's disease, tauopathies, and polyglutamine expansion diseases [e.g., Huntington's disease; and various spinocerebellar ataxias (SCAs), like SCA3]. There are no effective strategies to slow or prevent the neurodegeneration resulting from these diseases in humans. The mutations causing many proteinopathies (e.g., polyglutamine diseases and tauopathies) confer novel toxic functions on the specific protein, and disease severity frequently correlates with the expression levels of the protein. Thus, the factors regulating the synthesis and clearance of these aggregate-prone proteins are putative therapeutic targets. The proteasome and autophagy-lysosomal pathways are the major routes for mutant huntingtin fragment clearance. While the narrow proteasome barrel precludes entry of oligomers/aggregates of mutant huntingtin (or other aggregate-prone intracellular proteins), such substrates can be degraded by macroautophagy (which we will call autophagy). We showed that the autophagy inducer rapamycin reduced the levels of soluble and aggregated huntingtin and attenuated its toxicity in cells, and in transgenic Drosophila and mouse models. We extended the range of intracellular proteinopathy substrates that are cleared by autophagy to a wide range of other targets, including proteins mutated in certain SCAs, forms of alpha-synuclein mutated in familial forms of Parkinson's disease, and tau mutants that cause frontotemporal dementia/tauopathy. In this chapter, we consider the therapeutic potential of autophagy upregulation for various proteinopathies, and describe how this strategy may act both by removing the primary toxin (the misfolded/aggregate-prone protein) and by reducing susceptibility to apoptotic insults.
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PMID:Aggregate-prone proteins are cleared from the cytosol by autophagy: therapeutic implications. 1711 64

Immunohistochemical detection of protein components of pathological inclusions is widely used for neuropathological diagnosis of neurodegenerative disorders. However, different antibodies and antigen unmasking methods may account for variability between research studies and thus may affect diagnostic accuracy. Using two different antibodies raised against either a segment (184-200 aa) or the full length of human recombinant brain-specific tubulin polymerization promoting protein TPPP/p25, we immunohistochemically screened neurodegenerative disorders, both with and without pathological alpha-synuclein structures. We tested three different epitope unmasking methods, we applied laser confocal microscopy to evaluate double immunolabelling, and we compared the amount of structures exhibiting TPPP/p25 and alpha-synuclein immunoreactivity. We demonstrate that there are a variety of staining patterns depending on the epitope retrieval method and antibody used. The antibody raised against aa 184-200 segment of TPPP/p25 is better in immunolabelling the majority of alpha-synuclein immunopositive neuronal and glial pathological profiles detectable in Parkinson's disease, diffuse Lewy-body disease, and multiple system atrophy, in addition to immunostaining some extracellular huntingtin immunoreactive structures, lipofuscin, and neuromelanin particles. In contrast, the one raised against the full-length human recombinant TPPP/p25 is more suitable to immunodetect normal oligodendrocytes. Exposition of the segment aa 184-200 of TPPP/p25 in the aggregates of pathological inclusions renders this antibody a reliable marker of all types of alpha-synucleinopathies and suggests a role for TPPP/p25 in the aggregation process of some neurodegenerative conditions.
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PMID:The brain-specific protein TPPP/p25 in pathological protein deposits of neurodegenerative diseases. 1712 92

Trehalose, a disaccharide present in many non-mammalian species, protects cells against various environmental stresses. Whereas some of the protective effects may be explained by its chemical chaperone properties, its actions are largely unknown. Here we report a novel function of trehalose as an mTOR-independent autophagy activator. Trehalose-induced autophagy enhanced the clearance of autophagy substrates like mutant huntingtin and the A30P and A53T mutants of alpha-synuclein, associated with Huntington disease (HD) and Parkinson disease (PD), respectively. Furthermore, trehalose and mTOR inhibition by rapamycin together exerted an additive effect on the clearance of these aggregate-prone proteins because of increased autophagic activity. By inducing autophagy, we showed that trehalose also protects cells against subsequent pro-apoptotic insults via the mitochondrial pathway. The dual protective properties of trehalose (as an inducer of autophagy and chemical chaperone) and the combinatorial strategy with rapamycin may be relevant to the treatment of HD and related diseases, where the mutant proteins are autophagy substrates.
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PMID:Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. 1718 13

Previously, several studies have demonstrated changes in the levels of small heat shock proteins (sHSP) in the transgenic mouse models of familial amyotrophic lateral sclerosis (fALS) linked to mutations in Cu/Zn superoxide dismutase. Here, we compared the expression of sHSPs in transgenic mouse models of fALS, Parkinson's disease (PD), dentato-rubral pallido-luysian atrophy (DRPLA) and Huntington's disease (HD); where the expression of mutant cDNA genes was under the transcriptional regulation of the mouse prion protein promoter. These models express G37R mutant Cu/Zn superoxide dismutase (SOD1G37R; fALS), A53T mutant alpha-synuclein (alpha-SynA53T; PD), full-length mutant atrophin-1-65Q, and htt-N171-82Q (huntingtin N-terminal fragment; HD). We found that the levels and solubilities of two sHSPs, Hsp25 and alpha B-crystallin, were differentially regulated in these mice. Levels of both Hsp25 and alpha B-crystallin were markedly increased in subgroups of glias at the affected regions of symptomatic SODG37R and alpha-SynA53T transgenic mice; abnormal deposits or cells intensely positive for alpha B-crystallin were observed in SODG37R mice. By contrast, neither sHSP was induced in spinal cords of htt-N171-82Q or atrophin-1-65Q mice, which do not develop astrocytosis or major motor neuron abnormalities. Interestingly, the levels of insoluble alpha B-crystallin in spinal cords gradually increased as a function of age in nontransgenic animals. In vitro, alpha B-crystallin was capable of suppressing the aggregation of alpha-SynA53T, as previously described for a truncated mutant SOD1. The transgenes in these mice are expressed highly in astrocytes and thus our results suggest a role for small heat shock proteins in protecting activated glial cells such as astrocytes in neurodegenerative diseases.
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PMID:Differential regulation of small heat shock proteins in transgenic mouse models of neurodegenerative diseases. 1731 6

Transglutaminase catalyzes a covalent bond between peptide-bound glutamine residues and either lysine-bound peptide residues or mono- or polyamines. Multiple lines of evidence suggest that transglutaminase is involved in neurodegenerative diseases including Alzheimer disease, progressive supranuclear palsy, Huntington disease (HD), and Parkinson disease. In all of the neurodegenerative diseases examined to date, transglutaminase enzyme activity is upregulated in selectively vulnerable brain regions, transglutaminase proteins are associated with inclusion bodies characteristic of the diseases, and prominent proteins in the inclusion bodies are modified by transglutaminase enzymes. These prominent proteins in the inclusion bodies, including tau, alpha-synuclein, and huntingtin protein, are modified by transglutaminase in vitro and alpha-synuclein and huntingtin protein are modified in cells in culture. Similar changes in transglutaminase and transglutaminase-modified proteins are replicated in transgenic mouse models of the neurodegenerative diseases, including Huntington disease and progressive supranuclear palsy. Lastly, inhibition of transglutaminase either via drug treatments or molecular approaches is beneficial for the treatment of HD transgenic mice but has yet to be explored for the other neurodegenerative diseases. Further research is needed to determine the specific role(s) that transglutaminase plays in the pathophysiology of neurodegenerative diseases with possible implications for transglutaminase as a therapeutic target.
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PMID:Transglutaminase is linked to neurodegenerative diseases. 1741 16


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