Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation
Abstract Background PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfol...
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| Format: | Article |
| Language: | English |
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BMC
2017-08-01
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| Series: | Journal of Neuroinflammation |
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| Online Access: | http://link.springer.com/article/10.1186/s12974-017-0928-0 |
| _version_ | 1811328008232894464 |
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| author | Sylvia Torres-Odio Jana Key Hans-Hermann Hoepken Júlia Canet-Pons Lucie Valek Bastian Roller Michael Walter Blas Morales-Gordo David Meierhofer Patrick N. Harter Michel Mittelbronn Irmgard Tegeder Suzana Gispert Georg Auburger |
| author_facet | Sylvia Torres-Odio Jana Key Hans-Hermann Hoepken Júlia Canet-Pons Lucie Valek Bastian Roller Michael Walter Blas Morales-Gordo David Meierhofer Patrick N. Harter Michel Mittelbronn Irmgard Tegeder Suzana Gispert Georg Auburger |
| author_sort | Sylvia Torres-Odio |
| collection | DOAJ |
| description | Abstract Background PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types. Methods Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts. Results In a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”. Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3, and Nfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. Immunohistochemistry showed pronounced cellular response of Iba1-positive microglia and GFAP-positive astrocytes; brain lipidomics observed increases of ceramides as neuroinflammatory signs at old age. In a second approach, we assessed PINK1 deficiency in the presence of a stressor. Marked dysregulations of microbial defense factors Ifit3 and Rsad2 were consistently observed upon five analyses: (1) Pink1 −/− primary neurons in the first weeks after brain dissociation, (2) aged Pink1 −/− midbrain with transgenic A53T-alpha-synuclein overexpression, (3) human neuroblastoma cells with PINK1-knockdown and murine Pink1 −/− embryonal fibroblasts undergoing acute starvation, (4) triggering mitophagy in these cells with trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), and (5) subjecting them to pathogenic RNA-analogue poly(I:C). The stress regulation of MAVS, RSAD2, DDX58, IFIT3, IFIT1, and LRRK2 was PINK1 dependent. Dysregulation of some innate immunity genes was also found in skin fibroblast cells from PARK6 patients. Conclusions Thus, an individual biomarker with expression correlating to progression was not identified. Instead, more advanced disease stages involved additional pathways. Hence, our results identify PINK1 deficiency as an early modulator of innate immunity in neurons, which precedes late stages of neuroinflammation during alpha-synuclein spreading. |
| first_indexed | 2024-04-13T15:18:42Z |
| format | Article |
| id | doaj.art-37f1030eeb624662a92964439fd188fb |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-04-13T15:18:42Z |
| publishDate | 2017-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-37f1030eeb624662a92964439fd188fb2022-12-22T02:41:46ZengBMCJournal of Neuroinflammation1742-20942017-08-0114112610.1186/s12974-017-0928-0Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammationSylvia Torres-Odio0Jana Key1Hans-Hermann Hoepken2Júlia Canet-Pons3Lucie Valek4Bastian Roller5Michael Walter6Blas Morales-Gordo7David Meierhofer8Patrick N. Harter9Michel Mittelbronn10Irmgard Tegeder11Suzana Gispert12Georg Auburger13Experimental Neurology, Goethe University Medical SchoolExperimental Neurology, Goethe University Medical SchoolExperimental Neurology, Goethe University Medical SchoolExperimental Neurology, Goethe University Medical SchoolInstitute of Clinical Pharmacology, Goethe University Medical SchoolEdinger-Institute (Institute of Neurology), Goethe University Medical SchoolInstitute for Medical Genetics, Eberhard-Karls-University of TuebingenDepartment of Neurology, University Hospital San CecilioMax Planck Institute for Molecular GeneticsEdinger-Institute (Institute of Neurology), Goethe University Medical SchoolEdinger-Institute (Institute of Neurology), Goethe University Medical SchoolInstitute of Clinical Pharmacology, Goethe University Medical SchoolExperimental Neurology, Goethe University Medical SchoolExperimental Neurology, Goethe University Medical SchoolAbstract Background PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types. Methods Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts. Results In a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”. Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3, and Nfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. Immunohistochemistry showed pronounced cellular response of Iba1-positive microglia and GFAP-positive astrocytes; brain lipidomics observed increases of ceramides as neuroinflammatory signs at old age. In a second approach, we assessed PINK1 deficiency in the presence of a stressor. Marked dysregulations of microbial defense factors Ifit3 and Rsad2 were consistently observed upon five analyses: (1) Pink1 −/− primary neurons in the first weeks after brain dissociation, (2) aged Pink1 −/− midbrain with transgenic A53T-alpha-synuclein overexpression, (3) human neuroblastoma cells with PINK1-knockdown and murine Pink1 −/− embryonal fibroblasts undergoing acute starvation, (4) triggering mitophagy in these cells with trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), and (5) subjecting them to pathogenic RNA-analogue poly(I:C). The stress regulation of MAVS, RSAD2, DDX58, IFIT3, IFIT1, and LRRK2 was PINK1 dependent. Dysregulation of some innate immunity genes was also found in skin fibroblast cells from PARK6 patients. Conclusions Thus, an individual biomarker with expression correlating to progression was not identified. Instead, more advanced disease stages involved additional pathways. Hence, our results identify PINK1 deficiency as an early modulator of innate immunity in neurons, which precedes late stages of neuroinflammation during alpha-synuclein spreading.http://link.springer.com/article/10.1186/s12974-017-0928-0Parkinson’s diseaseUbiquitin kinase PINK1Mitochondrial dysfunctionAntiviral responseNeuroinflammation |
| spellingShingle | Sylvia Torres-Odio Jana Key Hans-Hermann Hoepken Júlia Canet-Pons Lucie Valek Bastian Roller Michael Walter Blas Morales-Gordo David Meierhofer Patrick N. Harter Michel Mittelbronn Irmgard Tegeder Suzana Gispert Georg Auburger Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation Journal of Neuroinflammation Parkinson’s disease Ubiquitin kinase PINK1 Mitochondrial dysfunction Antiviral response Neuroinflammation |
| title | Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation |
| title_full | Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation |
| title_fullStr | Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation |
| title_full_unstemmed | Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation |
| title_short | Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation |
| title_sort | progression of pathology in pink1 deficient mouse brain from splicing via ubiquitination er stress and mitophagy changes to neuroinflammation |
| topic | Parkinson’s disease Ubiquitin kinase PINK1 Mitochondrial dysfunction Antiviral response Neuroinflammation |
| url | http://link.springer.com/article/10.1186/s12974-017-0928-0 |
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