Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson's disease, Pick's disease, and Alzheimer's disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and mallory bodies in alcoholic liver disease

Lowe, James; Blanchard, Alexandre P.; Morrell, Ken; Lennox, Graham; Reynolds, Lindsay M.; Billett, M; Landon, Michael; Mayer, R. John

doi:10.1002/path.1711550105

Cited by 515 publications

(247 citation statements)

References 30 publications

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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.

131

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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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Section: The Upp and Long-term Synaptic Plasticitymentioning

confidence: 99%

The ubiquitin-proteasome pathway and synaptic plasticity

Hegde¹

2010

Learn. Mem.

131

123

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“…1, which is published as supporting information on the PNAS web site). Staining with hematoxylin͞eosin has largely been supplanted by immunolabeling for ubiquitin and ␣-synuclein (␣-SYN) (24,25), which more readily reveal LB and pale bodies, diffuse inclusions that are weakly stained with eosin. LB in the neocortex typically lack a halo (14) and may be inconspicuous with hematoxylin͞eosin.…”

Section: Description and Composition Of Lb Light Microscopymentioning

confidence: 99%

Lewy bodies

Shults

2006

Proc. Natl. Acad. Sci. U.S.A.

408

277

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Lewy bodies (LB) in the substantia nigra are a cardinal pathological feature of Parkinson's disease, but they occur in a number of neurodegenerative diseases and can be widespread in the nervous system. The characteristics, locations, and composition of LB are reviewed, with particular attention to ␣-synuclein (␣-SYN), which appears to be the major component of LB. The propensity for ␣-SYN, a presynaptic protein widely expressed in the brain, to aggregate is because of an amyloidogenic central region. The factors that favor the aggregation of ␣-SYN and mechanisms of toxicity are examined, and a mechanism through which aggregates of ␣-SYN could induce mitochondrial dysfunction and͞or release of proapoptotic molecules is proposed.

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“…Despite the recent interest in this field, a role for the ubiquitin system in neuronal physiology was first highlighted in chronic neurodegenerative disease. We have known for two decades that neuropathological inclusions in the majority of neurodegenerative diseases consistently contain ubiquitinated proteins, suggesting impairment of the UPS (Lowe et al, 1988). Genetic evidence also links ubiquitin system dysfunction to these diseases.…”

Section: Introductionmentioning

confidence: 99%

Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies

Bedford

Hay²,

Devoy³

et al. 2008

J. Neurosci.

295

254

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Ubiquitin-positive intraneuronal inclusions are a consistent feature of the major human neurodegenerative diseases, suggesting that dysfunction of the ubiquitin proteasome system is central to disease etiology. Research using inhibitors of the 20S proteasome to model Parkinson's disease is controversial. We report for the first time that specifically 26S proteasomal dysfunction is sufficient to trigger neurodegenerative disease. Here, we describe novel conditional genetic mouse models using the Cre/loxP system to spatially restrict inactivation of Psmc1 (Rpt2/S4) to neurons of either the substantia nigra or forebrain (e.g., cortex, hippocampus, and striatum). PSMC1 is an essential subunit of the 26S proteasome and Psmc1 conditional knock-out mice display 26S proteasome depletion in targeted neurons, in which the 20S proteasome is not affected. Impairment of specifically ubiquitin-mediated protein degradation caused intraneuronal Lewy-like inclusions and extensive neurodegeneration in the nigrostriatal pathway and forebrain regions. Ubiquitin and ␣-synuclein neuropathology was evident, similar to human Lewy bodies, but interestingly, inclusion bodies contained mitochondria. We support this observation by demonstrating mitochondria in an early form of Lewy body (pale body) from Parkinson's disease patients. The results directly confirm that 26S dysfunction in neurons is involved in the pathology of neurodegenerative disease. The model demonstrates that 26S proteasomes are necessary for normal neuronal homeostasis and that 20S proteasome activity is insufficient for neuronal survival. Finally, we are providing the first reproducible genetic platform for identifying new therapeutic targets to slow or prevent neurodegeneration.

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Cited by 515 publications

References 30 publications

The ubiquitin-proteasome pathway and synaptic plasticity

The ubiquitin-proteasome pathway and synaptic plasticity

Lewy bodies

Depletion of 26S Proteasomes in Mouse Brain Neurons Causes Neurodegeneration and Lewy-Like Inclusions Resembling Human Pale Bodies

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