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)

Amyloid deposits of the CNS caused clinical symptoms in four members of a Hungarian family. Histological investigations revealed a systemic disease, immunohistologically the deposited material was a transthyretin variant, DNA analysis showed a new transthyretin mutation (TTRAsp 18Gly). The disease--named meningocerebrovascular amyloidosis, Hungarian type--is inherited dominantly like other already known familial amyloidoses caused by transthyretin variants, however it does not cause the usual familial polyneuropathy but symptoms similar to those of the rare oculoleptomeningeal amyloidosis. The aim of the present study is to point to differential diagnosis. Its complaints, neurological signs and clinical findings which may be suspect of atypical migraine, brain tumour, chronic leptomeningitis or herpes encephalitis, multiple sclerosis and Parkinson disease are analysed and compared with those of other known types of familial amyloidoses. Attention is drawn to symmetrical calcification on CT scans. Skin biopsy may help the diagnosis. At present, therapy is only symptomatic.
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PMID:[Clinical characteristics of Hungarian-type familial meningo-cerebrovascular amyloidosis]. 899 35

Protein misfolding and aggregation have been linked to several human diseases, including Alzheimer's disease, Parkinson's disease, and systemic amyloidosis, by mechanisms that are not yet completely understood. The hallmark of most of these diseases is the formation of highly ordered and beta-sheet-rich aggregates referred to as amyloid fibrils. Fibril formation by WT transthyretin (TTR) or TTR variants has been linked to the etiology of systemic amyloidosis and familial amyloid polyneuropathy, respectively. Similarly, amyloid fibril formation by alpha-synuclein (alpha-syn) has been linked to neurodegeneration in Parkinson's disease, a movement disorder characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Here we show that consecutive cycles of compression-decompression under aggregating conditions lead to reversible dissociation of TTR and alpha-syn fibrils. The high sensitivity of amyloid fibrils toward high hydrostatic pressure (HHP) indicates the existence of packing defects in the fibril core. In addition, through the use of HHP we are able to detect differences in stability between fibrils formed from WT TTR and the familial amyloidotic polyneuropathy-associated variant V30M. The fibrils formed by WT alpha-syn were less susceptible to pressure denaturation than the Parkinson's disease-linked variants, A30P and A53T. This finding implies that fibrils of alpha-syn formed from the variants would be more easily dissolved into small oligomers by the cellular machinery. This result has physiological importance in light of the current view that the pathogenic species are the small aggregates rather the mature fibrils. Finally, the HHP-induced formation of fibrils from TTR is relatively fast (approximately 60 min), a quality that allows screening of antiamyloidogenic drugs.
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PMID:Dissociation of amyloid fibrils of alpha-synuclein and transthyretin by pressure reveals their reversible nature and the formation of water-excluded cavities. 1290 May 7

Protein misfolding has been shown to be the direct cause of a number of highly devastating diseases such as Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob syndrome, affecting the aging population globally. The deposition in tissues of amyloid fibrils is a characteristic of all these diseases, and the mechanisms by which these protein aggregates form continue to be intensively investigated. In only a fraction of cases is an underlying mutation responsible, and accordingly, what initiates amyloid formation in vivo is the major question that is addressed. In this study, we show that membranes containing phosphatidylserine (PS), a negatively charged phospholipid, induce a rapid formation of fibers by a variety of proteins, viz., lysozyme, insulin, glyceraldehyde-3-phosphate dehydrogenase, myoglobin, transthyretin, cytochrome c, histone H1, and alpha-lactalbumin. Congo red staining of these fibers yields the characteristic light green birefringence of amyloid, and fluorescent lipid tracers further reveal them to include phospholipids. Our results suggest that PS as well as other acidic phospholipids could provide the physiological low-pH environment on cellular membranes, enhancing protein fibril formation in vivo. Interestingly, all the proteins mentioned above either are cytotoxic or induce apoptosis. PS-protein interaction could be involved in the mechanism of cytotoxicity of the aggregated protein fibrils, perturbing membrane functions. Importantly, our results suggest that this process induced by acidic phospholipids may provide an unprecedented and generic connection between three current major areas of research: (i) mechanism(s) triggering amyloid formation, (ii) cytotoxicity of amyloidal protein aggregates, and (iii) mechanism(s) of action of cytotoxic proteins.
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PMID:Formation of amyloid fibers triggered by phosphatidylserine-containing membranes. 1530 28

DJ-1 plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to result in the onset of Parkinson's disease. DJ-1 has a protease-like structure and transthyretin (TTR), a protein causing familial amyloidotic polyneuropathy (FAP), was identified as a substrate for DJ-1 protease in this study. Both TTR and DJ-1 were secreted into the culture medium under normal conditions, and secreted TTR was not aggregated. Under oxidative conditions, TTR but not DJ-1 was secreted into the culture medium, resulting in aggregation. Mirror images of both the expression patterns and solubility of DJ-1 and TTR were observed in tissues of FAP patients, and an unoxidized form of DJ-1, an inactive form, was secreted into the serum of FAP patients. These results suggest that oxidative stress to cells abrogates secretion of DJ-1 and that secreted DJ-1 degrades aggregated TTR to protect against the onset of FAP.
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PMID:DJ-1 degrades transthyretin and an inactive form of DJ-1 is secreted in familial amyloidotic polyneuropathy. 1748 20

Amyloidogenesis is a characteristic feature of the 40 or so known protein deposition diseases, and accumulating evidence strongly suggests that self-association of misfolded proteins into either fibrils, protofibrils, or soluble oligomeric species is cytotoxic. The most likely mechanism for toxicity is through perturbation of membrane structure, leading to increased membrane permeability and eventual cell death. There have been a rather limited number of investigations of the interactions of amyloidogenic polypeptides and their aggregated states with membranes; these are briefly reviewed here. Amyloidogenic proteins discussed include A-beta from Alzheimer's disease, the prion protein, alpha-synuclein from Parkinson's disease, transthyretin (FAP, SSA amyloidosis), immunoglobulin light chains (primary (AL) amyloidosis), serum amyloid A (secondary (AA) amyloidosis), amylin or IAPP (Type 2 diabetes) and apolipoproteins. This review highlights the significant role played by fluorescence techniques in unraveling the nature of amyloid fibrils and their interactions and effects on membranes. Fluorescence spectroscopy is a valuable and versatile method for studying the complex mechanisms of protein aggregation, amyloid fibril formation and the interactions of amyloidogenic proteins with membranes. Commonly used fluorescent techniques include intrinsic and extrinsic fluorophores, fluorescent probes incorporated in the membrane, steady-state and lifetime measurements of fluorescence emission, fluorescence correlation spectroscopy, fluorescence anisotropy and polarization, fluorescence resonance energy transfer (FRET), fluorescence quenching, and fluorescence microscopy.
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PMID:Fluorescence as a method to reveal structures and membrane-interactions of amyloidogenic proteins. 1749 79

We have performed proteomic analysis in the cerebrospinal fluid in an animal model of Parkinson's disease induced by axotomy of the medial forebrain bundle. In this model, the degeneration of dopaminergic neurons was completed in 14 days, with a loss of about 50% dopaminergic neurons in the substantia nigra and a loss of more than 80% dopamine terminals in the striatum, with a similar diminution of dopamine levels in both structures. Proteins were separated by 2D electrophoresis and identified by matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF). We found significant increases of haptoglobin and transthyretin along with a decrease of Apo E concentrations in the cerebrospinal fluid of axotomized animals. Changes for haptoglobin and transthyretin were further confirmed in cerebrospinal fluid and plasma by Western blotting. These results suggest that monitoring plasma levels of these signals appears to be a promising biological marker of neuronal degeneration of the nigrostriatal dopaminergic system.
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PMID:Proteomic identification of biomarkers in the cerebrospinal fluid in a rat model of nigrostriatal dopaminergic degeneration. 1770 90

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

Conformational diseases, a general term comprising more than 40 disorders are caused by the accumulation of unfolded or misfolded proteins. Improper protein folding (misfolding) as well as accrual of unfolded proteins can lead to the formation of disordered (amorphous) or ordered (amyloid fibril) aggregates. The gradual accumulation of protein aggregates and the acceleration of their formation by stress explain the characteristic late or episodic onset of the diseases. The best studied in this group are neurodegenerative diseases and amyloidosis accompanied by the deposition of a specific aggregation-prone proteins or protein fragments and formation of insoluble fibrils. Amyloidogenic protein accumulation often occurs in the brain tissues, e.g. in Alzheimer's disease with the deposition of amyloid-beta and Tau, in scrapie and bovine spongiform encephalopathy with the accumulation of prion protein, in Parkinson's disease with the deposition of alpha-synuclein. Other examples of amyloid proteins are transthyretin, immunoglobulin light chain, gelsolin, etc. In addition to the brain, the accumulation of unfolded or misfolded proteins leading to pathology takes place in a wide variety of organs and tissues, including different parts of the eye. The best studied ocular conformational diseases are cataract in the lens and retinitis pigmentosa in the retina, but accumulation of misfolded proteins also occurs in other parts of the eye causing various disorders. Furthermore, ocular manifestation of systemic amyloidosis often causes the deposition of amyloidogenic proteins in different ocular tissues. Here we present the data regarding naturally unfolded and misfolded proteins in eye tissues, their structure-function relationships, and molecular mechanisms underlying their involvement in diseases. We also summarize the etiology of ocular conformational diseases and discuss approaches to their treatment.
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PMID:Conformational diseases: looking into the eyes. 1980 79

Alanine-to-threonine (A to T) substitutions caused by single nucleotide polymorphisms (SNPs) occur in diverse proteins, and in certain cases these substitutions induce self-aggregation into amyloid fibrils or aggregation in other amyloidogenic proteins. This is compatible with the inverse preferences of alanine to form helices and of threonine to support beta-sheet structures, which are crucial for amyloid fibrils formation. Our interest in these mutations was initiated by studying the potential effects of the A539T substitution in the butyrylcholinesterase BChE-K variant on amyloid fibrils formation in Alzheimer's disease. Other examples are, Parkinson's disease (PD), where A53T alpha-synuclein occurs in Lewy bodies and familial amyloid polyneuropathy (FAP), where an A25T substitution appears in transthyretin (TTR). In peripheral organs, an A34T substitution is found in the light chain immunoglobulin genes of patients with systemic amyloidosis and in familial hypercholesterolemia, an A370T substitution occurs in the LDLR regulator of cholesterol homeostasis. That such substitutions appear in proteins with important cellular functions suggests that they confer antagonistic pleiotropy, providing added value at an earlier age but causing damages and inducing amyloid diseases later on. This, in turn, may explain the evolutionary selection and preservation of these substitutions. The structural effect of residue substitutions and in particular A to T substitutions in amyloidogenic diseases thus merits further attention.
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PMID:Alanine-to-threonine substitutions and amyloid diseases: butyrylcholinesterase as a case study. 2006 Aug 16

We have searched for potential biomarkers in the cerebrospinal fluid (CSF) and plasma in an animal model of Parkinson's disease induced by inflammatory challenge. To achieve this, either unilateral or bilateral intranigral injection of lipopolysaccharide (LPS) was performed. CSF proteins were first analyzed either by 2D electrophoresis and MALDI-TOF at days 1 and 10 after the lesion to discern between potential prognosis and diagnosis protein markers. Most significant changes from this analysis were early increases of haptoglobin, transthyretin and different spots further identified as prostaglandin D synthase in response to LPS. These markers were then analyzed by western blotting in CSF and plasma using specific antibodies from samples obtained in animals receiving either LPS in substantia nigra or hippocampus and 6-OHDA in the medial forebrain bundle. This analysis confirmed the early increases of haptoglobin and transthyretin in response to intranigral injection of LPS or 6-OHDA in the bundle in plasma and CSF. We discuss the potential use of both biomarkers for the early diagnose of Parkinson's disease.
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PMID:Use of haptoglobin and transthyretin as potential biomarkers for the preclinical diagnosis of Parkinson's disease. 2055 85


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