Variant‐specific effects of GBA1 mutations on dopaminergic neuron proteostasis
Glucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H) GBA1 mutations have different PD phenotypes, with differences in age at disease onset, progression, and the sev...
| Prif Awduron: | , , , , , , , , , , |
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| Fformat: | Journal article |
| Iaith: | English |
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Wiley
2024
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| _version_ | 1826313591274340352 |
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| author | Onal, G Yalçın‐Çakmaklı, G Özçelik, CE Boussaad, I Şeker, UÖŞ Fernandes, HJR Demir, H Krüger, R Elibol, B Dökmeci, S Salman, MM |
| author_facet | Onal, G Yalçın‐Çakmaklı, G Özçelik, CE Boussaad, I Şeker, UÖŞ Fernandes, HJR Demir, H Krüger, R Elibol, B Dökmeci, S Salman, MM |
| author_sort | Onal, G |
| collection | OXFORD |
| description | Glucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H) GBA1 mutations have different PD phenotypes, with differences in age at disease onset, progression, and the severity of motor and non‐motor symptoms. We hypothesize that GBA1 mutations cause the accumulation of α‐synuclein by affecting the cross‐talk between cellular protein degradation mechanisms, leading to neurodegeneration. Accordingly, we tested whether mild and severe GBA1 mutations differentially affect the degradation of α‐synuclein via the ubiquitin–proteasome system (UPS), chaperone‐mediated autophagy (CMA), and macroautophagy and differentially cause accumulation and/or release of α‐synuclein. Our results demonstrate that endoplasmic reticulum (ER) stress and total ubiquitination rates were significantly increased in cells with severe GBA1 mutations. CMA was found to be defective in induced pluripotent stem cell (iPSC)‐derived dopaminergic neurons with mild GBA1 mutations, but not in those with severe GBA1 mutations. When examining macroautophagy, we observed reduced formation of autophagosomes in cells with the N370S and D409H GBA1 mutations and impairments in autophagosome–lysosome fusion in cells with the L444P GBA1 mutation. Accordingly, severe GBA1 mutations were found to trigger the accumulation and release of oligomeric α‐synuclein in iPSC‐derived dopaminergic neurons, primarily as a result of increased ER stress and defective macroautophagy, while mild GBA1 mutations affected CMA, which is mainly responsible for the degradation of the monomeric form of α‐synuclein. Overall, our findings provide new insight into the molecular basis of the clinical variability in PD associated with different GBA1 mutations. |
| first_indexed | 2024-09-25T04:15:39Z |
| format | Journal article |
| id | oxford-uuid:88d25cd7-5165-4b67-9e96-8f6576a013e1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:15:39Z |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | dspace |
| spelling | oxford-uuid:88d25cd7-5165-4b67-9e96-8f6576a013e12024-07-20T14:24:24ZVariant‐specific effects of GBA1 mutations on dopaminergic neuron proteostasisJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:88d25cd7-5165-4b67-9e96-8f6576a013e1EnglishJisc Publications RouterWiley2024Onal, GYalçın‐Çakmaklı, GÖzçelik, CEBoussaad, IŞeker, UÖŞFernandes, HJRDemir, HKrüger, RElibol, BDökmeci, SSalman, MMGlucocerebrosidase 1 (GBA1) mutations are the most important genetic risk factors for Parkinson's disease (PD). Clinically, mild (e.g., p.N370S) and severe (e.g., p.L444P and p.D409H) GBA1 mutations have different PD phenotypes, with differences in age at disease onset, progression, and the severity of motor and non‐motor symptoms. We hypothesize that GBA1 mutations cause the accumulation of α‐synuclein by affecting the cross‐talk between cellular protein degradation mechanisms, leading to neurodegeneration. Accordingly, we tested whether mild and severe GBA1 mutations differentially affect the degradation of α‐synuclein via the ubiquitin–proteasome system (UPS), chaperone‐mediated autophagy (CMA), and macroautophagy and differentially cause accumulation and/or release of α‐synuclein. Our results demonstrate that endoplasmic reticulum (ER) stress and total ubiquitination rates were significantly increased in cells with severe GBA1 mutations. CMA was found to be defective in induced pluripotent stem cell (iPSC)‐derived dopaminergic neurons with mild GBA1 mutations, but not in those with severe GBA1 mutations. When examining macroautophagy, we observed reduced formation of autophagosomes in cells with the N370S and D409H GBA1 mutations and impairments in autophagosome–lysosome fusion in cells with the L444P GBA1 mutation. Accordingly, severe GBA1 mutations were found to trigger the accumulation and release of oligomeric α‐synuclein in iPSC‐derived dopaminergic neurons, primarily as a result of increased ER stress and defective macroautophagy, while mild GBA1 mutations affected CMA, which is mainly responsible for the degradation of the monomeric form of α‐synuclein. Overall, our findings provide new insight into the molecular basis of the clinical variability in PD associated with different GBA1 mutations. |
| spellingShingle | Onal, G Yalçın‐Çakmaklı, G Özçelik, CE Boussaad, I Şeker, UÖŞ Fernandes, HJR Demir, H Krüger, R Elibol, B Dökmeci, S Salman, MM Variant‐specific effects of GBA1 mutations on dopaminergic neuron proteostasis |
| title | Variant‐specific effects of GBA1 mutations on dopaminergic neuron proteostasis |
| title_full | Variant‐specific effects of GBA1 mutations on dopaminergic neuron proteostasis |
| title_fullStr | Variant‐specific effects of GBA1 mutations on dopaminergic neuron proteostasis |
| title_full_unstemmed | Variant‐specific effects of GBA1 mutations on dopaminergic neuron proteostasis |
| title_short | Variant‐specific effects of GBA1 mutations on dopaminergic neuron proteostasis |
| title_sort | variant specific effects of gba1 mutations on dopaminergic neuron proteostasis |
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