Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteins
Abstract Mitochondrial dysfunction has been suggested to contribute to Parkinson’s disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultane...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-08-01
|
| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-023-00564-3 |
| _version_ | 1797453499995258880 |
|---|---|
| author | Chun Chen David McDonald Alasdair Blain Emily Mossman Kiera Atkin Michael F. Marusich Roderick Capaldi Laura Bone Anna Smith Andrew Filby Daniel Erskine Oliver Russell Gavin Hudson Amy E. Vincent Amy K. Reeve |
| author_facet | Chun Chen David McDonald Alasdair Blain Emily Mossman Kiera Atkin Michael F. Marusich Roderick Capaldi Laura Bone Anna Smith Andrew Filby Daniel Erskine Oliver Russell Gavin Hudson Amy E. Vincent Amy K. Reeve |
| author_sort | Chun Chen |
| collection | DOAJ |
| description | Abstract Mitochondrial dysfunction has been suggested to contribute to Parkinson’s disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultaneously study multiple related proteins within human brain tissue. We used imaging mass cytometry (IMC) to overcome these challenges, measuring multiple protein targets, whilst retaining the spatial relationship between targets in post-mortem midbrain sections. We used IMC to simultaneously interrogate subunits of the mitochondrial oxidative phosphorylation complexes, and several key signalling pathways important for mitochondrial homoeostasis, in a large cohort of PD patient and control cases. We revealed a generalised and synergistic reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson’s patients. Further, protein-protein abundance relationships appeared significantly different between PD and disease control tissue. Our data showed a significant reduction in the abundance of PINK1, Parkin and phosphorylated ubiquitinSer65, integral to the mitophagy machinery; two mitochondrial chaperones, HSP60 and PHB1; and regulators of mitochondrial protein synthesis and the unfolded protein response, SIRT3 and TFAM. Further, SIRT3 and PINK1 did not show an adaptive response to an ATP synthase defect in the Parkinson’s neurons. We also observed intraneuronal aggregates of phosphorylated ubiquitinSer65, alongside increased abundance of mitochondrial proteases, LONP1 and HTRA2, within the Parkinson’s neurons with Lewy body pathology, compared to those without. Taken together, these findings suggest an inability to turnover mitochondria and maintain mitochondrial proteostasis in Parkinson’s neurons. This may exacerbate the impact of oxidative phosphorylation defects and ageing related oxidative stress, leading to neuronal degeneration. Our data also suggest that that Lewy pathology may affect mitochondrial quality control regulation through the disturbance of mitophagy and intramitochondrial proteostasis. |
| first_indexed | 2024-03-09T15:23:44Z |
| format | Article |
| id | doaj.art-bfa8380617db4f5b96e684c21887a732 |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-09T15:23:44Z |
| publishDate | 2023-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-bfa8380617db4f5b96e684c21887a7322023-11-26T12:40:44ZengNature Portfolionpj Parkinson's Disease2373-80572023-08-019111410.1038/s41531-023-00564-3Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteinsChun Chen0David McDonald1Alasdair Blain2Emily Mossman3Kiera Atkin4Michael F. Marusich5Roderick Capaldi6Laura Bone7Anna Smith8Andrew Filby9Daniel Erskine10Oliver Russell11Gavin Hudson12Amy E. Vincent13Amy K. Reeve14Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversityInnovation, Methodology and Application Research Theme, Biosciences Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversitymAbDx, Inc.Cellstate BiosciencesWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversityInnovation, Methodology and Application Research Theme, Biosciences Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Biosciences Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversityWellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle UniversityAbstract Mitochondrial dysfunction has been suggested to contribute to Parkinson’s disease pathogenesis, though an understanding of the extent or exact mechanism of this contribution remains elusive. This has been complicated by challenging nature of pathway-based analysis and an inability simultaneously study multiple related proteins within human brain tissue. We used imaging mass cytometry (IMC) to overcome these challenges, measuring multiple protein targets, whilst retaining the spatial relationship between targets in post-mortem midbrain sections. We used IMC to simultaneously interrogate subunits of the mitochondrial oxidative phosphorylation complexes, and several key signalling pathways important for mitochondrial homoeostasis, in a large cohort of PD patient and control cases. We revealed a generalised and synergistic reduction in mitochondrial quality control proteins in dopaminergic neurons from Parkinson’s patients. Further, protein-protein abundance relationships appeared significantly different between PD and disease control tissue. Our data showed a significant reduction in the abundance of PINK1, Parkin and phosphorylated ubiquitinSer65, integral to the mitophagy machinery; two mitochondrial chaperones, HSP60 and PHB1; and regulators of mitochondrial protein synthesis and the unfolded protein response, SIRT3 and TFAM. Further, SIRT3 and PINK1 did not show an adaptive response to an ATP synthase defect in the Parkinson’s neurons. We also observed intraneuronal aggregates of phosphorylated ubiquitinSer65, alongside increased abundance of mitochondrial proteases, LONP1 and HTRA2, within the Parkinson’s neurons with Lewy body pathology, compared to those without. Taken together, these findings suggest an inability to turnover mitochondria and maintain mitochondrial proteostasis in Parkinson’s neurons. This may exacerbate the impact of oxidative phosphorylation defects and ageing related oxidative stress, leading to neuronal degeneration. Our data also suggest that that Lewy pathology may affect mitochondrial quality control regulation through the disturbance of mitophagy and intramitochondrial proteostasis.https://doi.org/10.1038/s41531-023-00564-3 |
| spellingShingle | Chun Chen David McDonald Alasdair Blain Emily Mossman Kiera Atkin Michael F. Marusich Roderick Capaldi Laura Bone Anna Smith Andrew Filby Daniel Erskine Oliver Russell Gavin Hudson Amy E. Vincent Amy K. Reeve Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteins npj Parkinson's Disease |
| title | Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteins |
| title_full | Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteins |
| title_fullStr | Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteins |
| title_full_unstemmed | Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteins |
| title_short | Parkinson’s disease neurons exhibit alterations in mitochondrial quality control proteins |
| title_sort | parkinson s disease neurons exhibit alterations in mitochondrial quality control proteins |
| url | https://doi.org/10.1038/s41531-023-00564-3 |
| work_keys_str_mv | AT chunchen parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT davidmcdonald parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT alasdairblain parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT emilymossman parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT kieraatkin parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT michaelfmarusich parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT roderickcapaldi parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT laurabone parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT annasmith parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT andrewfilby parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT danielerskine parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT oliverrussell parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT gavinhudson parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT amyevincent parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins AT amykreeve parkinsonsdiseaseneuronsexhibitalterationsinmitochondrialqualitycontrolproteins |