| Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: Implication for protein aggregation and immune response. | |
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MedLine Citation:
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PMID: 22033150 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The ubiquitin-proteasome system (UPS) is the major intracellular proteolytic mechanism controlling the degradation of misfolded/abnormal proteins. A common hallmark in amyotrophic lateral sclerosis (ALS) and in other neurodegenerative disorders is the accumulation of misfolded/abnormal proteins into the damaged neurons, leading to the formation of cellular inclusions that are mostly ubiquitin-positive. Although proteolysis is a complex mechanism requiring the participation of different pathways, the abundant accumulation of ubiquitinated proteins strongly suggests an important contribution of UPS to these neuropathological features. The use of cellular and animal models of ALS, particularly those expressing mutant SOD1, the gene mutation most represented in familiar ALS, has provided significant evidence for a role of UPS in protein inclusions formation and motor neuron death. This review will specifically discuss this piece of evidence and provide suggestions of potential strategies for therapeutic intervention. We will also discuss the finding that, unlike the constitutive proteasome subunits, the inducible subunits are overexpressed early during disease progression in SOD1 mice models of ALS. These subunits form the immunoproteasome and generate peptides for the major histocompatibility complex class I molecules, suggesting a role of this system in the immune responses associated with the pathological features of ALS. Since recent discoveries indicate that innate and adaptive immunity may influence the disease process, in this review we will also provide evidence of a possible connection between immune-inflammatory reactions and UPS function, in the attempt to better understand the etiopathology of ALS and to identify appropriate targets for novel treatment strategies of this devastating disease. |
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Authors:
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Caterina Bendotti; Marianna Marino; Cristina Cheroni; Elena Fontana; Valeria Crippa; Angelo Poletti; Silvia De Biasi |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-10-20 |
Journal Detail:
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Title: Progress in neurobiology Volume: - ISSN: 1873-5118 ISO Abbreviation: - Publication Date: 2011 Oct |
Date Detail:
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Created Date: 2011-10-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370121 Medline TA: Prog Neurobiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011. Published by Elsevier Ltd. |
Affiliation:
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Laboratory of Molecular Neurobiology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Via La Masa, 19, 20156 Milano, Italy. |
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