The 20S proteasome isolated from Alzheimer’s disease brain shows post‐translational modifications but unchanged proteolytic activity

Gillardon, Frank; Kloß, Alexander; Berg, Matthias; Neumann, Manuela; Mechtler, Karl; Hengerer, Bastian; Dahlmann, Burkhardt

doi:10.1111/j.1471-4159.2006.04438.x

Cited by 42 publications

(28 citation statements)

References 31 publications

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“…Proteasome activity is reduced by up to 50% in Alzheimer's disease and other neurodegenerative diseases which are characterized by the accumulation of abnormal protein, for example amyloid-b [43][44][45]. Proteasome function may be restored by blocking production of abnormal protein or by chromatographic purification of 20S proteasomes [46][47][48].…”

Section: The Proteasomementioning

confidence: 98%

The therapeutic potential of the proteasome in leukaemia

McCloskey

McMullin²,

Walker

et al. 2008

Hematological Oncology

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Many cellular processes converge on the proteasome, and its key regulatory role is increasingly being recognized. Proteasome inhibition allows the manipulation of many cellular pathways including apoptotic and cell cycle mechanisms. The proteasome inhibitor bortezomib has enhanced responses in newly diagnosed patients with myeloma and provides a new line of therapy in relapsed and refractory patients. Malignant cells are more sensitive to proteasome inhibition than normal haematopoietic cells. Proteasome inhibition enhances many conventional therapies and its role in leukaemia is promising.

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Section: The Proteasomementioning

confidence: 98%

The therapeutic potential of the proteasome in leukaemia

McCloskey

McMullin²,

Walker

et al. 2008

Hematological Oncology

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“…Alzheimer's disease (AD) and Parkinson's disease (PD) data show a correlation of decreased proteasomal concentration with deposition of neurofibrillary tangles and amyloid plaques (Olanow and McNaught 2006;Cecarini et al 2007;Gillardon et al 2007). The ubiquitin-proteasome pathway is also reported to be involved in the aging of the brain (Keller et al 2000a, b).…”

Section: Introductionmentioning

confidence: 98%

Circulating Extracellular Proteasome in the Cerebrospinal Fluid: A Study on Concentration and Proteolytic Activity

et al. 2011

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Alterations of the intracellular ubiquitin-proteasome pathway are found in neurodegenerative and inflammatory disorders of the central nervous system, as well as in its malignancies. Inhibitory substrates of the proteasomes represent promising approaches to control autoimmune inflammations and induction of apoptosis in cancer cells. Extracellular circulating proteasomes are positively correlated to outcome prognosis in hematogenic neoplasias and the outcome in critically ill patients. Previously, we reported raised levels of proteolytic active 20S proteasomes in the extracellular alveolar space in patients with acute respiratory distress syndrome (ARDS). For the cerebrospinal fluid, we assumed that extracellular circulating proteasomes with enzymatic activity can be found, too. Cerebrospinal fluid (CSF) samples of twenty-six patients (14 females, 12 males), who underwent diagnostic spinal myelography, were analyzed for leukocyte cell count, total protein content, lactate and interleukine-6 (Il-6) concentrations. CSF samples were analyzed for concentration and enzymatic activity of extracellular 20S proteasomes (fluorescenic substrate cleavage; femtokatal). Blood samples were analyzed with respect to concentration of extracellular circulating proteasomes. Choroidal plexus was harvested at autopsies and examined with immunoelectron microscopy (EM) for identification of possible transportation mechanisms. Statistical analysis was performed using SPSS (18.0.3). In all patients, extracellular proteasome was found in the CSF. The mean concentration was 24.6 ng/ml. Enzymatic activity of the 20S subunits of proteasomes was positively identified by the fluorescenic subtrate cleavage at a mean of 8.5 fkat/ml. Concentrations of extracellular proteasomes in the CSF, total protein content and Il-6 were uncorrelated. Immunoelectron microscopy revealed merging vesicles of proteasomes with the outer cell membrane suggestive of an exozytic transport mechanism. For the first time, extracellular circulating 20S proteasome in the CSF of healthy individuals is identified and its enzymatic activity detected. A possible exozytic vesicle-bond transportation mechanism is suggested by immunoelectron microscopy. The present study raises more questions on the function of extracellular proteasome in the CSF and encourages further studies on the role of extracellular protesomes in pathological conditions of the central nervous system (tumor lesions and inflammatory processes).

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“…When chaperone levels are too high or too low, some substrates that are particularly difficult to handle can begin to accumulate and cause disease. These substrates can then have detrimental consequences to the proteostasis system and general cellular health (62)(63)(64)(65).…”

Section: Methodsmentioning

confidence: 99%

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

et al. 2013

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Aggregation of tau protein in the brain is associated with a class of neurodegenerative diseases known as tauopathies. FK506 binding protein 51 kDa (FKBP51, encoded by FKBP5) forms a mature chaperone complex with Hsp90 that prevents tau degradation. In this study, we have shown that tau levels are reduced throughout the brains of Fkbp5 -/-mice. Recombinant FKBP51 and Hsp90 synergized to block tau clearance through the proteasome, resulting in tau oligomerization. Overexpression of FKBP51 in a tau transgenic mouse model revealed that FKBP51 preserved the species of tau that have been linked to Alzheimer's disease (AD) pathogenesis, blocked amyloid formation, and decreased tangle load in the brain. Alterations in tau turnover and aggregate structure corresponded with enhanced neurotoxicity in mice. In human brains, FKBP51 levels increased relative to age and AD, corresponding with demethylation of the regulatory regions in the FKBP5 gene. We also found that higher FKBP51 levels were associated with AD progression. Our data support a model in which age-associated increases in FKBP51 levels and its interaction with Hsp90 promote neurotoxic tau accumulation. Strategies aimed at attenuating FKBP51 levels or its interaction with Hsp90 have the potential to be therapeutically relevant for AD and other tauopathies.

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The 20S proteasome isolated from Alzheimer’s disease brain shows post‐translational modifications but unchanged proteolytic activity

Cited by 42 publications

References 31 publications

The therapeutic potential of the proteasome in leukaemia

The therapeutic potential of the proteasome in leukaemia

Circulating Extracellular Proteasome in the Cerebrospinal Fluid: A Study on Concentration and Proteolytic Activity

Accelerated neurodegeneration through chaperone-mediated oligomerization of tau

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