EGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson’s disease
Abstract Parkinson’s disease (PD), characterized by α-synuclein accumulation in dopaminergic neurons, is a common neurodegenerative disorder. Recent findings highlight DNAJB1 as a crucial factor in the disaggregation of α-synuclein fibrils in vitro, yet the underlying mechanisms and regulatory proce...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-06-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-01006-y |
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| author | Yun-Yu Huang Sue-Jane Lin Wei-Yu Chiang Yuan-Teng Chang Chan-Chih Yang Chia-Yu Liao Ya-Lan Chang Chin-Hsien Lin Shu-Chun Teng |
| author_facet | Yun-Yu Huang Sue-Jane Lin Wei-Yu Chiang Yuan-Teng Chang Chan-Chih Yang Chia-Yu Liao Ya-Lan Chang Chin-Hsien Lin Shu-Chun Teng |
| author_sort | Yun-Yu Huang |
| collection | DOAJ |
| description | Abstract Parkinson’s disease (PD), characterized by α-synuclein accumulation in dopaminergic neurons, is a common neurodegenerative disorder. Recent findings highlight DNAJB1 as a crucial factor in the disaggregation of α-synuclein fibrils in vitro, yet the underlying mechanisms and regulatory processes in neuronal cells remain largely undefined. This study reveals that DNAJB1 facilitates the clearance of α-synuclein via the Hsp70 chaperone system. Phosphorylation of DNAJB1 at tyrosine 5 by the epidermal growth factor receptor (EGFR) is essential for mitigating α-synuclein aggregation, enhancing its interaction with Hsp70. Dysregulation of this pathway disrupts α-synuclein delivery to Hsp70, worsening aggregation in neuronal cells. Analysis of human brain lysates from individuals with PD and unaffected controls showed reduced levels of EGFR and DNAJB1, with an increase in phosphorylated DNAJB1 at Y5. These findings elucidate mechanisms in PD pathology and suggest DNAJB1 as a promising candidate for targeted therapeutic strategies. |
| format | Article |
| id | doaj-art-f54dbd2a82d540d8b74eb5bde21be24d |
| institution | Kabale University |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-f54dbd2a82d540d8b74eb5bde21be24d2025-08-20T03:26:42ZengNature Portfolionpj Parkinson's Disease2373-80572025-06-0111111610.1038/s41531-025-01006-yEGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson’s diseaseYun-Yu Huang0Sue-Jane Lin1Wei-Yu Chiang2Yuan-Teng Chang3Chan-Chih Yang4Chia-Yu Liao5Ya-Lan Chang6Chin-Hsien Lin7Shu-Chun Teng8Department of Microbiology, College of Medicine, National Taiwan UniversityDepartment of Microbiology, College of Medicine, National Taiwan UniversityDepartment of Microbiology, College of Medicine, National Taiwan UniversityDepartment of Microbiology, College of Medicine, National Taiwan UniversityDepartment of Microbiology, College of Medicine, National Taiwan UniversityDepartment of Microbiology, College of Medicine, National Taiwan UniversityDepartment of Microbiology, College of Medicine, National Taiwan UniversityDepartment of Neurology, National Taiwan University Hospital TaipeiDepartment of Microbiology, College of Medicine, National Taiwan UniversityAbstract Parkinson’s disease (PD), characterized by α-synuclein accumulation in dopaminergic neurons, is a common neurodegenerative disorder. Recent findings highlight DNAJB1 as a crucial factor in the disaggregation of α-synuclein fibrils in vitro, yet the underlying mechanisms and regulatory processes in neuronal cells remain largely undefined. This study reveals that DNAJB1 facilitates the clearance of α-synuclein via the Hsp70 chaperone system. Phosphorylation of DNAJB1 at tyrosine 5 by the epidermal growth factor receptor (EGFR) is essential for mitigating α-synuclein aggregation, enhancing its interaction with Hsp70. Dysregulation of this pathway disrupts α-synuclein delivery to Hsp70, worsening aggregation in neuronal cells. Analysis of human brain lysates from individuals with PD and unaffected controls showed reduced levels of EGFR and DNAJB1, with an increase in phosphorylated DNAJB1 at Y5. These findings elucidate mechanisms in PD pathology and suggest DNAJB1 as a promising candidate for targeted therapeutic strategies.https://doi.org/10.1038/s41531-025-01006-y |
| spellingShingle | Yun-Yu Huang Sue-Jane Lin Wei-Yu Chiang Yuan-Teng Chang Chan-Chih Yang Chia-Yu Liao Ya-Lan Chang Chin-Hsien Lin Shu-Chun Teng EGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson’s disease npj Parkinson's Disease |
| title | EGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson’s disease |
| title_full | EGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson’s disease |
| title_fullStr | EGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson’s disease |
| title_full_unstemmed | EGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson’s disease |
| title_short | EGFR phosphorylates DNAJB1 to suppress α-synuclein aggregation in Parkinson’s disease |
| title_sort | egfr phosphorylates dnajb1 to suppress α synuclein aggregation in parkinson s disease |
| url | https://doi.org/10.1038/s41531-025-01006-y |
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