Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway
The ubiquitin–proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a ma...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
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Nature Publishing Group
2017
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| Online Access: | https://eprints.nottingham.ac.uk/39767/ |
| _version_ | 1848795909236719616 |
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| author | Ugun-Klusek, Aslihan Tatham, Michael H. Elkharaz, Jamal Constantin-Teodosiu, Dumitru Lawler, Karen Mohamed, Hala Paine, Simon M.L. Anderson, Glen John Mayer, R. Lowe, James Ellen Billett, E. Bedford, Lynn |
| author_facet | Ugun-Klusek, Aslihan Tatham, Michael H. Elkharaz, Jamal Constantin-Teodosiu, Dumitru Lawler, Karen Mohamed, Hala Paine, Simon M.L. Anderson, Glen John Mayer, R. Lowe, James Ellen Billett, E. Bedford, Lynn |
| author_sort | Ugun-Klusek, Aslihan |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | The ubiquitin–proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2. Early events also include phosphorylation of p62/SQSTM1 (p62) and increased optineurin, as well as autophagosomal LC3B and removal of some mitochondria, supporting the induction of selective autophagy. Inhibition of the degradation of ubiquitinated MOM proteins with continued 26S proteasome dysfunction at later stages may impede efficient mitophagy. However, continued 26S proteasome dysfunction also decreases the levels of essential autophagy proteins ATG9 and LC3B, which is characterised by decreases in their gene expression, ultimately leading to impaired autophagy. Intriguingly, serine 351 phosphorylation of p62 did not enhance its binding to Keap1 or stabilise the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor in this neuronal context. Nrf2 protein levels were markedly decreased despite transcriptional activation of the Nrf2 gene. Our study reveals novel insights into the interplay between the UPS and autophagy in neurons and is imperative to understanding neurodegenerative disease where long-term proteasome inhibition has been implicated. |
| first_indexed | 2025-11-14T19:39:34Z |
| format | Article |
| id | nottingham-39767 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:39:34Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-397672020-05-04T18:31:41Z https://eprints.nottingham.ac.uk/39767/ Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway Ugun-Klusek, Aslihan Tatham, Michael H. Elkharaz, Jamal Constantin-Teodosiu, Dumitru Lawler, Karen Mohamed, Hala Paine, Simon M.L. Anderson, Glen John Mayer, R. Lowe, James Ellen Billett, E. Bedford, Lynn The ubiquitin–proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2. Early events also include phosphorylation of p62/SQSTM1 (p62) and increased optineurin, as well as autophagosomal LC3B and removal of some mitochondria, supporting the induction of selective autophagy. Inhibition of the degradation of ubiquitinated MOM proteins with continued 26S proteasome dysfunction at later stages may impede efficient mitophagy. However, continued 26S proteasome dysfunction also decreases the levels of essential autophagy proteins ATG9 and LC3B, which is characterised by decreases in their gene expression, ultimately leading to impaired autophagy. Intriguingly, serine 351 phosphorylation of p62 did not enhance its binding to Keap1 or stabilise the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor in this neuronal context. Nrf2 protein levels were markedly decreased despite transcriptional activation of the Nrf2 gene. Our study reveals novel insights into the interplay between the UPS and autophagy in neurons and is imperative to understanding neurodegenerative disease where long-term proteasome inhibition has been implicated. Nature Publishing Group 2017-01-05 Article PeerReviewed Ugun-Klusek, Aslihan, Tatham, Michael H., Elkharaz, Jamal, Constantin-Teodosiu, Dumitru, Lawler, Karen, Mohamed, Hala, Paine, Simon M.L., Anderson, Glen, John Mayer, R., Lowe, James, Ellen Billett, E. and Bedford, Lynn (2017) Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway. Cell Death and Disease, 8 (1). e2531/1-e2531/12. ISSN 2041-4889 http://www.nature.com/cddis/journal/v8/n1/full/cddis2016443a.html doi:10.1038/cddis.2016.443 doi:10.1038/cddis.2016.443 |
| spellingShingle | Ugun-Klusek, Aslihan Tatham, Michael H. Elkharaz, Jamal Constantin-Teodosiu, Dumitru Lawler, Karen Mohamed, Hala Paine, Simon M.L. Anderson, Glen John Mayer, R. Lowe, James Ellen Billett, E. Bedford, Lynn Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway |
| title | Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway |
| title_full | Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway |
| title_fullStr | Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway |
| title_full_unstemmed | Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway |
| title_short | Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway |
| title_sort | continued 26s proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the keap1-nrf2 oxidative defence pathway |
| url | https://eprints.nottingham.ac.uk/39767/ https://eprints.nottingham.ac.uk/39767/ https://eprints.nottingham.ac.uk/39767/ |