Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular chaperones and heat shock proteins (Hsp) have emerged as critical regulators of proteins associated with neurodegenerative disease pathologies. The very nature of the chaperone system, which is to maintain protein quality control, means that most nascent proteins come in contact with chaperone proteins. Thus, amyloid precursor protein (APP), members of the gamma-secretase complex (presenilin 1 [PS1] collectively), the microtubule-associated protein tau (MAPT) as well as a number of neuroinflammatory components are all in contact with chaperones from the moment of their production. Chaperones are often grouped together as one machine presenting abnormal or mutant proteins to the proteasome for degradation, but this is not at all the case. In fact, the chaperone family consists of more than 100 proteins in mammalian cells, and the primary role for most of these proteins is to protect clients following synthesis and during stress; only as a last resort do they facilitate protein degradation. To the best of our current knowledge, the chaperone system in eukaryotic cells revolves around the ATPase activities of Hsp70 and Hsp90, the two primary chaperone scaffolds. Other chaperones and co-chaperones manipulate the ATPase activities of Hsp70 and Hsp90, facilitating either folding of the client or its degradation. In the case of Alzheimer's disease (AD), a number of studies have recently emerged describing the impact that these chaperones have on the proteotoxic effects of tau and amyloid- beta accumulation. Here, we present the current understandings of chaperone biology and examine the literature investigating these proteins in the context of AD.
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PMID:Chaperone signalling complexes in Alzheimer's disease. 1944 61

Amyloid beta-peptide (Abeta) has a central role in the pathogenesis of Alzheimer's disease (AD). Cellular cholesterol homeostasis regulates endoproteolytic generation of Abeta from the amyloid precursor protein (APP). Previous studies have identified acyl-coenzyme A: cholesterol acyltransferase (ACAT), an enzyme that regulates subcellular cholesterol distribution, as a potential therapeutic target for AD. Inhibition of ACAT activity decreases Abeta generation in cell- and animal-based models of AD through an unknown mechanism. Here we show that ACAT inhibition retains a fraction of APP molecules in the early secretory pathway, limiting the availability of APP for secretase-mediated proteolytic processing. ACAT inhibitors delayed the trafficking of immature APP molecules from the endoplasmic reticulum (ER) as shown by metabolic labeling and live-cell imaging. This resulted in partial ER retention of APP and enhanced ER-associated degradation of APP by the proteasome, without activation of the unfolded protein response pathway. The ratio of mature APP to immature APP was reduced in brains of mice treated with ACAT inhibitors, and strongly correlated with reduced brain APP-C99 and cerebrospinal fluid Abeta levels in individual animals. Our results identify a novel ACAT-dependent mechanism that regulates secretory trafficking of APP, likely contributing to decreased Abeta generation in vivo.
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PMID:Inhibition of acyl-coenzyme A: cholesterol acyl transferase modulates amyloid precursor protein trafficking in the early secretory pathway. 1962 58

Human neurodegenerative diseases with abnormal protein aggregates are associated with aberrant post-translational modifications, solubility, aggregation and fibril formation of selected proteins which cannot be degraded by cytosolic proteases, ubiquitin-protesome system and autophagy, and, therefore, accumulate in cells and extracellular compartments as residual debris. In addition to the accumulation of "primary" proteins, several other mechanisms are involved in the degenerative process and probably may explain crucial aspects such as the timing, selective cellular vulnerability and progression of the disease in particular individuals. One of these mechanisms is oxidative stress, which occurs in the vast majority of, if not all, degenerative diseases of the nervous system. The present review covers most of the protein targets that have been recognized as modified proteins mainly using bidimensional gel electrophoresis, Western blotting with oxidative and nitrosative markers, and identified by mass spectrometry in Alzheimer disease; certain tauopathies such as progressive supranuclear palsy, Pick disease, argyrophilic grain disease and frontotemporal lobar degeneration linked to mutations in tau protein, for example, FTLD-tau, Parkinson disease and related alpha-synucleinopathies; Huntington disease; and amyotrophic lateral sclerosis, together with related animal and cellular models. Vulnerable proteins can be mostly grouped in defined metabolic pathways covering glycolysis and energy metabolism, cytoskeletal, chaperoning, cellular stress responses, and members of the ubiquitin-proteasome system. Available information points to the fact that vital metabolic pathways are hampered by protein oxidative damage in several human degenerative diseases and that oxidative damage occurs at very early stages of the disease. Yet parallel functional studies are limited and further work is needed to document whether protein oxidation results in loss of activity and impaired performance. A better understanding of proteins susceptible to oxidation and nitration may serve to define damaged metabolic networks at early stages of disease and to advance therapeutic interventions to attenuate disease progression.
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PMID:Protein targets of oxidative damage in human neurodegenerative diseases with abnormal protein aggregates. 1972 34

Alzheimer's disease (AD) is a devastating neurodegenerative disease, the most common among the dementing illnesses. The neuropathological hallmarks of AD include extracellular beta-amyloid (amyloid precursor protein (APP) deposits, intracellular neurofibrillary tangles (NFT)), dystrophic neuritis and amyloid angiopathy. The mismetabolism of APP and the defective clearance of beta amyloid generate a cascade of events including hyperphosphorylated tau (tau) mediated breakdown of microtubular assembly and resultant synaptic failure which results in AD. The exact aetiopathogenesis of AD is still obscure. The preeminent hypotheses of AD include amyloid cascade hypothesis and tau hyperphosphorylation. The amyloid hypothesis states that extracellular amyloid plaques formed by aggregates of Abeta peptide generated by the proteolytic cleavages of APP are central to AD pathology. Intracellular assembly states of the oligomeric and protofibrillar species may facilitate tau hyperphosphorylation, disruption of proteasome and mitochondria function, dysregulation of calcium homeostasis, synaptic failure, and cognitive dysfunction. The tau hypothesis states that excessive or abnormal phosphorylation of tau results in the transformation of normal adult tau into PHF-tau (paired helical filament) and NFTs. Vascular hypothesis is also proposed for AD and it concludes that advancing age and the presence of vascular risk factors create a Critically Attained Threshold of Cerebral Hypoperfusion (CATCH) which leads to cellular and subcellular pathology involving protein synthesis, development of plaques, inflammatory response, and synaptic damage leading to the manifestations of AD. Multiple other aetiological and pathogenetic hypotheses have been put forward including genetics, oxidative stress, dysfunctional calcium homeostasis, hormonal, inflammatory-immunologic, and cell cycle dysregulation with the resultant neurotransmitter dysfunctions and cognitive decline. The available therapeutic agents target only the neurotransmitter dysfunction in AD and agents specifically targeting the pathogenetic mechanisms like amyloid deposition and tau hyperphosphorylation might provide a definite therapeutic edge.
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PMID:Neurobiology of Alzheimer's disease. 1974 93

FE65 is a neural adaptor protein known to interact with a number of proteins, including Alzheimer's amyloid beta-protein precursor (APP). Although several different functions have been proposed for FE65, its primary physiological role remains unclear. We previously showed that APP can liberate FE65 from the membrane as a result of APP phosphorylation, and that the liberated FE65 translocates into the nuclei of osmotically stressed cells. Within the nucleus, FE65 formed a patched structure at the nuclear matrix, which facilitated the induction of gammaH2AX [Nakaya T, Kawai T & Suzuki T (2008) J Biol Chem283, 19119-19131]. Here, we report that the tumor suppressor p53 is colocalized with FE65 in the nuclear patches and is stabilized by FE65 in sorbitol-treated cells. In FE65 knockdown cells, protein levels of p53 targeted to the nuclear matrix were rapidly decreased through the proteasome degradation pathway after sorbitol treatment, as compared with control cells. These results suggest that the translocation of FE65 to the nuclear matrix, along with the formation of nuclear patches, is required for the stabilization of p53 by its suppression of the proteasome degradation pathway, thus facilitating the subsequent induction of gammaH2AX in osmotically stressed cells.
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PMID:Metabolic stabilization of p53 by FE65 in the nuclear matrix of osmotically stressed cells. 1979 71

Synapse loss is strongly correlated with cognitive impairment in Alzheimer's disease (AD). We have previously reported the loss of dendritic spines and the presence of dystrophic neurites in both the hippocampi of transgenic mice overexpressing amyloid precursor protein (APP) and in the human brain affected with AD. In the studies reported here we have asked whether the acute alterations in dendritic spines induced by Abeta, as well as the chronic loss of spine density seen in hAPP transgenic mice, are reversible by treatments that restore the cAMP/PKA/CREB signaling pathway or proteasome function to control levels. The results show that both rolipram and TAT-HA-Uch-L1 restore spine density to near control conditions, even in elderly mice. The results suggest that changes in dendritic structure and function that occur after Abeta elevation are reversible even after long periods of time, and that one could envision therapeutic approaches to AD based on this restoration that could work independently of therapies aimed at lowering Abeta levels in the brain.
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PMID:Reversal of long-term dendritic spine alterations in Alzheimer disease models. 1980 89

Sporadic forms of Alzheimer's and Parkinson's diseases are the most frequent forms of their kind. Together with Huntington's disease, they belong to the so called 'conformational diseases' as they share a common feature in the accumulation of insoluble protein deposits. In this review, we focus on the significance of the ubiquitin-proteasome system in conformational diseases and the possible consequences due to the accumulation of aberrant proteins. In all forms of Alzheimer's and Huntington's diseases, but not in Parkinson's disease, we have shown the presence of misframed proteins such as misframed ubiquitin (UBB(+1)) of which we have determined the functional relevance in vitro and in vivo.Misframed proteins are the result of the inaccurate transcription of monotonic sequences in the genome and their subsequent translation. This process has been called 'molecular misreading'. In the present review, we will discuss the present state of the art with regard to UBB(+1) and amyloid precursor protein APP(+1).
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PMID:Misframed proteins and neurodegeneration: a novel view on Alzheimer's and Parkinson's diseases. 2017 31

Tau is the major protein exhibiting intracellular accumulation in Alzheimer disease. The mechanisms leading to its accumulation are not fully understood. It has been proposed that the proteasome is responsible for degrading tau but, since proteasomal inhibitors block both the ubiquitin-dependent 26S proteasome and the ubiqutin-independent 20S proteasome pathways, it is not clear which of these pathways is involved in tau degradation. Some involvement of the ubiquitin ligase, CHIP in tau degradation has also been postulated during stress. In the current studies, we utilized HT22 cells and tau-transfected E36 cells in order to test the relative importance or possible requirement of the ubiquitin-dependent 26S proteasomal system versus the ubiquitin-independent 20S proteasome, in tau degradation. By means of ATP-depletion, ubiquitinylation-deficient E36ts20 cells, a 19S proteasomal regulator subunit MSS1-siRNA approaches, and in vitro ubiquitinylation studies, we were able to demonstrate that ubiquitinylation is not required for normal tau degradation.
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PMID:Tau protein degradation is catalyzed by the ATP/ubiquitin-independent 20S proteasome under normal cell conditions. 2047 62

Alzheimer's disease (AD) is a neurodegenerative disorder that represents the most common type of dementia in the elderly. One of the hallmarks of this disease is a progressive accumulation of amyloid fibrils in senile plaques (SPs), which are composed principally of amyloid-beta peptides (Abeta). The 4-kDa beta-amyloid peptides are produced from the beta-amyloid precursor protein (APP) through sequential processing by beta- and gamma-secretase enzymes in the amyloidogenic pathway. By an alternative non-amyloidogenic pathway, mediated by alpha- and gamma-secretases enzymes, APP is processed within the Abeta domain. Both processing pathways may result in the generation of a fragment called APP intracellular C-terminal domain (AICD) which is hypothesized to contribute to the pathophysiology of AD. Experimental evidence highlights that biological functions of AICD are mediated by interactions between its YENPTY motif and specific binding factors. We critically reviewed literature concerning physiological function of this proteolitic fragment, mainly focusing on their degradation by the two best characterized systems, proteasome and IDE (insulin degrading enzyme). Our work is aimed to analyse the functional role of AICD, integrating also the AICD degradation processes, to better define a potential role of AICD in signal transduction.
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PMID:beta-Amyloid precursor protein metabolism: focus on the functions and degradation of its intracellular domain. 2056 99

Beta-amyloid peptide (Abeta) is generated via sequential proteolysis of amyloid precursor protein (APP) by beta- and gamma-secretases. Cell-based screening experiments disclosed that the MEK (MAP kinase kinase) inhibitors, U0126 and PD184352, suppress Abeta secretion from human neuronal SH-SY5Y cells expressing Swedish mutant APP. These inhibitors did not affect the cellular levels of APP but significantly reduced those of the APP beta-C-terminal fragment (beta-CTF). Additionally, beta-CTF levels were markedly reduced by these inhibitors in cells expressing the fragment in a gamma-secretase-independent and proteasome-dependent manner. Our results suggest that MEK inhibitors reduce Abeta generation via secretase-independent alteration of beta-CTF levels.
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PMID:MEK inhibitors suppress beta-amyloid production by altering the level of a beta-C-terminal fragment of amyloid precursor protein in neuronal cells. 2060 8


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