Ubiquitin Is a Component of Paired Helical Filaments in Alzheimer's Disease

Mori, Hiroshi; Kondo, Jun; Ihara, Yasuo

doi:10.1126/science.3029875

Cited by 803 publications

(333 citation statements)

References 22 publications

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“…116 In AD brain, the paired helical filaments (PHF) in tangles are ubiquitinated. 117,118 The level of ubiquitin in AD cerebral cortex is increased several-fold and correlates with the amount of neurofibrillary changes. 119 Using an ELISA method based on the monoclonal antibody 5-25, raised against PHF from AD brains, 120 Mehta and co-workers reported in 1985 high levels of "paired helical filaments antigen" in CSF in AD.…”

Section: Ubiquitinmentioning

confidence: 99%

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

2004

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Summary:The introduction of acetylcholine esterase (AChE) inhibitors as a symptomatic treatment of Alzheimer's disease (AD) has made patients seek medical advice at an earlier stage of the disease. This has highlighted the importance of diagnostic markers for early AD. However, there is no clinical method to determine which of the patients with mild cognitive impairment (MCI) will progress to AD with dementia, and which have a benign form of MCI without progression. In this paper, the performance of cerebrospinal fluid (CSF) protein biomarkers for AD is reviewed. The diagnostic performance of the three biomarkers, total tau, phospho-tau, and the 42 amino acid form of ␤-amyloid have been evaluated in numerous studies and their ability to identify incipient AD in MCI cases has also been studied. Some candidate AD biomarkers including ubiquitin, neurofilament proteins, growth-associated protein 43 (neuromodulin), and neuronal thread protein (AD7c) show interesting results but have been less extensively studied. It is concluded that CSF biomarkers may have clinical utility in the differentiation between AD and several important differential diagnoses, including normal aging, depression, alcohol dementia, and Parkinson's disease, and also in the identification of Creutzfeldt-Jakob disease in cases with rapidly progressive dementia. Early diagnosis of AD is not only of importance to be able to initiate symptomatic treatment with AChE inhibitors, but will be the basis for initiation of treatment with drugs aimed at slowing down or arresting the degenerative process, such as ␥-secretase inhibitors, if these prove to affect AD pathology and to have a clinical effect.

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Section: Ubiquitinmentioning

confidence: 99%

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

2004

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“…Although ubiquitin was used as a marker for brain pathology, such as neurofibrillary tangles in Alzheimer's disease and Lewy bodies in Parkinson's disease (Mori et al 1987;Lowe et al 1988), no physiological or pathological role for ubiquitin in the nervous system was found until about a decade and a half ago. The first discovery of ubiquitin-proteasome-mediated degradation of a substrate relevant to synaptic plasticity in the nervous system was that of R subunits of PKA (Hegde et al 1993).…”

Section: The Upp and Long-term Synaptic Plasticitymentioning

confidence: 99%

The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

129

123

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Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wideranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for degradation by a multisubunit complex called the proteasome. Linkage of ubiquitin to protein substrates is highly specific and occurs through a series of well-orchestrated enzymatic steps. The UPP regulates neurotransmitter receptors, protein kinases, synaptic proteins, transcription factors, and other molecules critical for synaptic plasticity. Accumulating evidence indicates that the operation of the UPP in neurons is not homogeneous and is subject to tightly managed local regulation in different neuronal subcompartments. Investigations on both invertebrate and vertebrate model systems have revealed local roles for enzymes that attach ubiquitin to substrate proteins, as well as for enzymes that remove ubiquitin from substrates. The proteasome also has been shown to possess disparate functions in different parts of the neuron. Here I give a broad overview of the role of the UPP in synaptic plasticity and highlight the local roles and regulation of the proteolytic pathway in neurons.

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“…Among these proteins, ubiquitin has been known to be the most constantly and robustly immunopositive in LBs, glial cytoplasmic inclusions, and other related lesions together with ␣-synuclein. The presence of ubiquitin in intracellular inclusions in synucleinopathies suggests that abnormally aggregated or misfolded proteins are targeted for ubiquitination in these inclusions in a similar fashion to tau in neurofibrillary tangles of Alzheimer's disease (24,25). Recently, Shimura et al (19) reported that glycosylated ␣-synuclein (␣Sp22) can be readily multiubiquitinated by parkin that functions as E3 ubiquitin ligase in vitro.…”

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confidence: 99%

Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy Lesions

Hasegawa

Fujiwara

Nonaka

et al. 2002

Journal of Biological Chemistry

392

293

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␣-Synuclein is one of the major components of intracellular fibrillary aggregates in the brains of a subset of neurodegenerative disorders, including Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and Hallervorden-Spatz disease, which are referred to as ␣-synucleinopathies. We have shown previously (Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K., and Iwatsubo, T. (2002) Nat. Cell Biol. 4, 160-164) that ␣-synuclein deposited in synucleinopathy brains is extensively phosphorylated at Ser-129 and migrates at 15 kDa. Here we examined the biochemical characteristics of the additional, higher molecular mass species of phosphorylated ␣-synuclein-positive polypeptides that also are recovered in the Sarkosylinsoluble fraction of synucleinopathy and migrate at about 22 and 29 kDa. These 22 and 29 kDa bands were positive for three different anti-ubiquitin antibodies and comigrated perfectly with in vitro ubiquitinated ␣-synuclein that may correspond to mono-and diubiquitinated ␣-synuclein, respectively. Furthermore, cyanogen bromide cleavage of the 22 and 29 kDa polypeptides shifted the mobility to 19 and 26 kDa, respectively, and they retained immunoreactivity for both ubiquitin and ␣-synuclein. Finally, protein sequence analysis showed that the 19 kDa band contained two amino-terminal sequences of ␣-synuclein and ubiquitin. These results strongly suggest that phosphorylated ␣-synuclein is targeted to mono-and diubiquitination in synucleinopathy brains, which may have implications for mechanisms of these diseases.Lewy bodies (LBs) 1 and related neuritic changes (Lewy neurites; LNs) are the defining neuropathological characteristics of Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The discovery of point mutations in the ␣-synuclein gene in some pedigrees with an autosomal dominantly inherited familial PD (1, 2), together with the identification of ␣-synuclein as the major component of abnormal filaments in LBs and LNs in the brains of patients with PD and DLB (3-6), strongly implicated ␣-synuclein in the pathogenesis of these neurodegenerative disorders. Immunohistochemical and biochemical studies using anti-␣-synuclein antibodies revealed that ␣-synuclein is deposited in other types of filamentous inclusions, including glial or neuronal cytoplasmic inclusions in multiple system atrophy (MSA) (7-9), Lewy body-like inclusions, and dystrophic neurites in Hallervorden-Spatz disease (HSD) (10, 11), leading to the collective nomenclature of "␣-synucleinopathies" for these disorders. Recent biochemical studies have shown that the full-length ␣-synuclein is deposited as abnormal filaments (9, 12), which are recovered in detergent (i.e. Triton X and Sarkosyl)-insoluble fractions of brains of patients with synucleinopathy but not in control brains (13-15). We and others have shown that insoluble ␣-synuclein from synucleinopathic brains as well as in vitro assembled filaments from recombinant ␣-synuclein are highly resistant to prot...

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Ubiquitin Is a Component of Paired Helical Filaments in Alzheimer's Disease

Cited by 803 publications

References 22 publications

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

Cerebrospinal fluid protein biomarkers for Alzheimer’s disease

The ubiquitin-proteasome pathway and synaptic plasticity

Phosphorylated α-Synuclein Is Ubiquitinated in α-Synucleinopathy Lesions

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