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Proteasome inhibition by paired helical filament-tau in brains of patients with Alzheimer's disease

Published on Feb 28, 2003in Journal of Neurochemistry4.87
· DOI :10.1046/j.1471-4159.2003.01642.x
Susi Keck2
Estimated H-index: 2
,
Robert Nitsch57
Estimated H-index: 57
+ 1 AuthorsOliver Ullrich33
Estimated H-index: 33
Cite
Abstract
Alzheimer's disease (AD) is characterized neuropathologically by intracellular neurofibrillary tangles (NFTs) formed of tau-based paired helical filaments (PHFs) and extracellular β-amyloid plaques. The degree of Alzheimer dementia correlates with the severity of PHFs and NFTs. As an intraneuronal accumulation of oxidatively damaged proteins has been found in the brains of patients with AD, a dysfunction of the proteasomal system, which degrades damaged proteins, has been assumed to cause protein aggregation and therefore neurodegeneration in AD. In this study, we revealed that such proteasome dysfunction in AD brain results from the inhibitory binding of PHF-tau to proteasomes. We analysed the proteasome activity in brains from patients with AD and age-matched controls, and observed a significant decrease to 56% of the control level in the straight gyrus of patients with AD. This loss of activity was not associated with a decrease in the proteasome protein. PHF-tau co-precipitated during proteasome immunoprecipitation and proteasome subunits could be co-isolated during isolation of PHFs from AD brain. Furthermore, the proteasome activity in human brains strongly correlated with the amount of co-precipitated PHF-tau during immunoprecipitation of proteasome. Incubation of isolated proteasomes with PHF-tau isolated from AD brain, and with PHFs after in vitro assembly from human recombinant tau protein, resulted in a distinct inhibition of proteasome activity by PHF-tau. As this inhibition of proteasome activity was sufficient to induce neuronal degeneration and death, we suggest that PHF-tau is able directly to induce neuronal damage in the AD brain.
  • References (33)
  • Citations (312)
Cite
References33
Newest
Published on Jan 25, 2006in Annals of the New York Academy of Sciences4.29
L.A. MacKENZIE Ingano1
Estimated H-index: 1
(Harvard University),
Kristen M. Lentini2
Estimated H-index: 2
(Harvard University)
+ 2 AuthorsDora M. Kovacs32
Estimated H-index: 32
(Harvard University)
Published on Jan 1, 2003
Neil F. Bence11
Estimated H-index: 11
,
Roopal M. Sampat1
Estimated H-index: 1
,
Ron R. Kopito59
Estimated H-index: 59
Intracellular deposition of aggregated and ubiquitylated proteins is a prominent cytopathological feature of most neurodegenerative disorders. Whether protein aggregates themselves are pathogenic or are the consequence of an underlying molecular lesion is unclear. Here, we report that protein aggregation directly impaired the function of the ubiquitin-proteasome system. Transient expression of two unrelated aggregation-prone proteins, a huntingtin fragment containing a pathogenic polyglutamine r...
Published on Dec 25, 2001in Journal of Neurochemistry4.87
Jeffrey N. Keller58
Estimated H-index: 58
,
Keith B. Hanni8
Estimated H-index: 8
,
William R. Markesbery109
Estimated H-index: 109
Abstract : Inhibition of proteasome activity is sufficient to induce neuron degeneration and death ; however, altered proteasome activity in a neurodegenerative disorder has not been demonstrated. In the present study, we analyzed proteasome activity in short-postmortem-interval autopsied brains from 16 Alzheimer's disease (AD) and nine age- and sex-matched controls. A significant decrease in proteasome activity was observed in the hippocampus and parahippocampal gyrus (48%), superior and middle...
Published on Oct 1, 2001in Nature Medicine30.64
Kenny K.K. Chung20
Estimated H-index: 20
(JHUSOM: Johns Hopkins University School of Medicine),
Yi Zhang21
Estimated H-index: 21
(JHUSOM: Johns Hopkins University School of Medicine)
+ 6 AuthorsTed M. Dawson138
Estimated H-index: 138
(JHUSOM: Johns Hopkins University School of Medicine)
Parkin ubiquitinates the α-synuclein–interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease
Published on Oct 1, 2001in Nature Medicine30.64
Aaron Ciechanover86
Estimated H-index: 86
(Technion – Israel Institute of Technology)
One neuronal characteristic of Parkinson disease is the presence of Lewy bodies–intracytoplasmic accumulations of protein. A new study draws a molecular link between the formation of these bodies, the ubiquitin protein degradation system, parkin and synphilin-1. (pages 1144–1150)
Published on Sep 1, 2001in Journal of Molecular Medicine
Keiji Tanaka108
Estimated H-index: 108
,
Toshiaki Suzuki13
Estimated H-index: 13
+ 3 AuthorsYoshikuni Mizuno78
Estimated H-index: 78
(Juntendo University)
Autosomal recessive juvenile parkinsonism (AR-JP) is one of the most common forms of familial Parkinson's disease. AR-JP is characterized by selective and massive loss of dopaminergic neurons in the substantia nigra of the midbrain and absence of Lewy bodies, the pathological hallmark of idiopathic Parkinson's disease. Parkin, the causative gene of AR-JP, encodes a 52-kDa protein that is a RING-type ubiquitin (Ub) protein ligase (E3) collaborating with a Ub-conjugating enzyme (E2) belonging to a...
Published on Mar 23, 2001in Journal of Biological Chemistry
Peter Lasch35
Estimated H-index: 35
(CUNY: City University of New York),
Tobias Petras6
Estimated H-index: 6
(CUNY: City University of New York)
+ 3 AuthorsTilman Grune67
Estimated H-index: 67
(CUNY: City University of New York)
Abstract Proteins exposed to oxidative stress are degraded via proteolytic pathways. In the present study, we undertook a series of in vitro experiments to establish a correlation between the structural changes induced by mild oxidation of the model protein RNase A and the proteolytic rate found upon exposure of the modified protein toward the isolated 20 S proteasome. Fourier transform infrared spectroscopy was used as a structure-sensitive probe. We report here strong experimental evidence for...
Published on Dec 1, 2000in The FASEB Journal5.39
Nicolle Sitte30
Estimated H-index: 30
,
Katrin Merker12
Estimated H-index: 12
+ 2 AuthorsTilman Grune67
Estimated H-index: 67
(SC: University of Southern California)
Oxidized/cross-linked intracellular protein materials, known as ceroid pigment, age pigment, or lipofuscin, accumulate in postmitotic tissues. It is unclear, however, whether diminishing proteolytic capacities play a role in the accumulation of such oxidized intracellular proteins. Previous studies revealed that the proteasome is responsible for the degradation of most oxidized soluble cytoplasmic and nuclear proteins and, we propose, for the prevention of such damage accumulations. The present ...
Published on Nov 1, 2000in Nature43.07
Pedro Fernandez-Funez15
Estimated H-index: 15
,
Maria Laura Nino-Rosales1
Estimated H-index: 1
+ 12 AuthorsPamela J. Skinner22
Estimated H-index: 22
(UMN: University of Minnesota)
A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease1. Spinocerebellar ataxia type 1 (SCA1) is one such disease—caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this group of diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Drosophila. Here we sho...
Published on Oct 15, 2000in Journal of Neuroscience Research4.14
Mariella Lpez Salon1
Estimated H-index: 1
(UBA: University of Buenos Aires),
Laura Morelli21
Estimated H-index: 21
(UBA: University of Buenos Aires)
+ 2 AuthorsJuana M. Pasquini30
Estimated H-index: 30
(UBA: University of Buenos Aires)
Alzheimer’s disease (AD) is characterized by the presence of neurofibrillary tangles (NFT), senile plaques, and cerebrovascular deposits of amyloid-b. Ubiquitin has also been shown to be present in some of the inclusions characteristic of this disease. To obtain further insight into the role played by the ubiquitin pathway in AD, we investigated the capacity of postmortem samples of cerebral cortex from normal and AD patients to form high-molecular-weight ubiquitin‐ protein conjugates. Activity ...
Cited By312
Newest
Published on Dec 1, 2019in Acta neuropathologica communications
Niraj M. Shanbhag3
Estimated H-index: 3
(UCSF: University of California, San Francisco),
Mark D. Evans + 6 AuthorsLennart Mucke87
Estimated H-index: 87
(UCSF: University of California, San Francisco)
The maintenance of genomic integrity is essential for normal cellular functions. However, it is difficult to maintain over a lifetime in postmitotic cells such as neurons, in which DNA damage increases with age and is exacerbated by multiple neurological disorders, including Alzheimer’s disease (AD). Here we used immunohistochemical staining to detect DNA double strand breaks (DSBs), the most severe form of DNA damage, in postmortem brain tissues from patients with mild cognitive impairment (MCI...
Published on Jun 18, 2019in Journal of Cellular Biochemistry3.45
Sunil Thomas13
Estimated H-index: 13
(Lankenau Institute for Medical Research),
Kevther Hoxha (Lankenau Institute for Medical Research)+ 1 AuthorsGeorge C. Prendergast62
Estimated H-index: 62
(Thomas Jefferson University)
Published on Sep 8, 2019in bioRxiv
Roy G Muriu (Kansas City University of Medicine and Biosciences), Jessica M Sage4
Estimated H-index: 4
(Kansas City University of Medicine and Biosciences),
Abdulbaki Agbas12
Estimated H-index: 12
(Kansas City University of Medicine and Biosciences)
Aim: Platelets provide substantial information about the proteolytic system profile in neurodegenerative diseases. Assessment of autophagy and proteasome activities in platelets may reflect tissue proteolytic system profile in the central nervous system in Alzheimer diseases (AD). We aimed to demonstrate the optimum assay conditions and identify target proteins in platelet proteolytic system. Methods: Autophagosome forming proteins were identified by Western blotting analysis. Standard gel elect...
Published on Sep 1, 2019in Journal of Molecular Biology5.07
Yu Ye (University of Cambridge), David Klenerman52
Estimated H-index: 52
(University of Cambridge),
Daniel Finley65
Estimated H-index: 65
(Harvard University)
Abstract Aggregation of amyloidogenic proteins is an abnormal biological process implicated in neurodegenerative disorders. While the aggregation process of amyloid-forming proteins has been studied extensively, the mechanism of aggregate removal is poorly understood. We recently demonstrated that proteasomes could fragment filamentous aggregates into smaller entities, restricting aggregate size (Cliffe et al., 2019 [1] ). Here, we show in vitro that UBE2W can modify the N-terminus of both αS an...
Published on Feb 1, 2019in Molecular Neurobiology4.59
Mehdi Mirzaei16
Estimated H-index: 16
(Macquarie University),
Kanishka Pushpitha (Macquarie University)+ 15 AuthorsAngela Godinez (Macquarie University)
Increased amyloid β (Aβ) aggregation is a hallmark feature of Alzheimer’s disease (AD) pathology. The APP/PS1 mouse model of AD exhibits accumulation of Aβ in the retina and demonstrates reduced retinal function and other degenerative changes. The overall molecular effects of AD pathology on the retina remain undetermined. Using a proteomics approach, this study assessed the molecular effects of Aβ accumulation and progression of AD pathology on the retina. Retinal tissues from younger (2.5 mont...
Published on Jun 1, 2019in Neuroscience Letters2.17
Jiqing Cao1
Estimated H-index: 1
(ISMMS: Icahn School of Medicine at Mount Sinai),
Margaret B. Zhong (Columbia University)+ 2 AuthorsDongming Cai15
Estimated H-index: 15
Abstract Several lines of evidence have shown that defects in the endo-lysosomal autophagy degradation pathway and the ubiquitin-proteasome system play a role in Alzheimer's Disease (AD) pathogenesis and pathophysiology. Early pathological changes, such as marked enlargement of endosomal compartments, gradual accumulation of autophagic vacuoles (AVs) and lysosome dyshomeostasis, are well-recognized in AD. In addition to these pathological indicators, many genetic variants of key regulators in th...
Published on May 29, 2019in bioRxiv
Yu Ye (University of Cambridge), David Klenerman52
Estimated H-index: 52
(University of Cambridge),
Daniel Finley65
Estimated H-index: 65
(Harvard University)
Aggregation of amyloidogenic proteins is an abnormal biological process implicated in neurodegenerative disorders. While the aggregation process of amyloid-forming proteins has been studied extensively, the mechanism of aggregate removal is poorly understood. We recently demonstrated that proteasomes could fragment filamentous aggregates into smaller entities, restricting aggregate size[1]. Here, we show in vitro that UBE2W can modify the N-terminus of both α-synuclein and tau K18 with a single ...
Published on May 1, 2019in Journal of Nutritional Biochemistry4.49
Marcus O. W. Grimm27
Estimated H-index: 27
(Saarland University),
Anna Lauer1
Estimated H-index: 1
(Saarland University)
+ 9 AuthorsR Bals17
Estimated H-index: 17
(Saarland University)
Abstract A vast majority of the elderly population shows a mild to moderate vitamin D deficiency. Besides the well-known function of vitamin D, vitamin D receptor is also expressed in brain and is discussed to regulate several genes. However very little is known whether genes are regulated, associated with Alzheimer’s disease (AD). Here we investigate 117 genes, known to be affected in AD, in mouse brain samples with a mild vitamin D hypovitaminosis comparable to the vitamin D status of the elde...
Published on Apr 1, 2019in Journal of Proteomics3.54
Ewa Laskowska14
Estimated H-index: 14
(University of Gdańsk),
Dorota Kuczyńska-Wiśnik8
Estimated H-index: 8
(University of Gdańsk),
Barbara Lipinska20
Estimated H-index: 20
(University of Gdańsk)
Abstract Protein homeostasis (proteostasis) refers to the ability of cells to preserve the correct balance between protein synthesis, folding and degradation. Proteostasis is essential for optimal cell growth and survival under stressful conditions. Various extracellular and intracellular stresses including heat shock, oxidative stress, proteasome malfunction, mutations and aging-related modifications can result in disturbed proteostasis manifested by enhanced misfolding and aggregation of prote...