TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis
Abstract Cell-to-cell propagation of α-synuclein is thought to be the underlying mechanism of Parkinson’s disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propa...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-07-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-022-00789-x |
| _version_ | 1797233738647601152 |
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| author | Eun-Jin Bae Minsun Choi Jeong Tae Kim Dong-Kyu Kim Min Kyo Jung Changyoun Kim Tae-Kyung Kim Jun Sung Lee Byung Chul Jung Soo Jean Shin Ka Hyun Rhee Seung-Jae Lee |
| author_facet | Eun-Jin Bae Minsun Choi Jeong Tae Kim Dong-Kyu Kim Min Kyo Jung Changyoun Kim Tae-Kyung Kim Jun Sung Lee Byung Chul Jung Soo Jean Shin Ka Hyun Rhee Seung-Jae Lee |
| author_sort | Eun-Jin Bae |
| collection | DOAJ |
| description | Abstract Cell-to-cell propagation of α-synuclein is thought to be the underlying mechanism of Parkinson’s disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propagation of aggregates remains unknown. Here, using in vitro cultures, we found that soluble factors secreted from activated microglia promote cell-to-cell propagation of α-synuclein and further showed that among these soluble factors, TNF-α had the most robust stimulatory activity. Treatment of neurons with TNF-α triggered cellular senescence, as shown by transcriptomic analyses demonstrating induction of senescence-associated genes and immunoanalysis of senescence phenotype marker proteins. Interestingly, secretion of α-synuclein was increased in senescent neurons, reflecting acquisition of a senescence-associated secretory phenotype (SASP). Using vacuolin-1, an inhibitor of lysosomal exocytosis, and RNAi against rab27a, we demonstrated that the SASP was mediated by lysosomal exocytosis. Correlative light and electron microscopy and immunoelectron microscopy confirmed that propagating α-synuclein aggregates were present in electron-dense lysosome-like compartments. TNF-α promoted the SASP through stimulation of lysosomal exocytosis, thereby increasing the secretion of α-synuclein. Collectively, these results suggest that TNF-α is the major inflammatory factor that drives cell-to-cell propagation of α-synuclein by promoting the SASP and subsequent secretion of α-synuclein. |
| first_indexed | 2024-04-24T16:20:57Z |
| format | Article |
| id | doaj.art-4731767c2b954ccca338bf9cebf0f22d |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-04-24T16:20:57Z |
| publishDate | 2022-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-4731767c2b954ccca338bf9cebf0f22d2024-03-31T11:11:33ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132022-07-0154678880010.1038/s12276-022-00789-xTNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosisEun-Jin Bae0Minsun Choi1Jeong Tae Kim2Dong-Kyu Kim3Min Kyo Jung4Changyoun Kim5Tae-Kyung Kim6Jun Sung Lee7Byung Chul Jung8Soo Jean Shin9Ka Hyun Rhee10Seung-Jae Lee11Neuroscience Research Institute, Seoul National University College of MedicineDepartment of Biomedical Sciences, Seoul National University College of MedicineDepartment of Biomedical Sciences, Seoul National University College of MedicineNeuroscience Research Institute, Seoul National University College of MedicineNeural Circuits Research Group, Korea Brain Research InstituteNeuroscience Research Institute, Seoul National University College of MedicineNeuroscience Research Institute, Seoul National University College of MedicineNeuroscience Research Institute, Seoul National University College of MedicineNeuroscience Research Institute, Seoul National University College of MedicineDepartment of Biomedical Sciences, Seoul National University College of MedicineDepartment of Biomedical Sciences, Seoul National University College of MedicineNeuroscience Research Institute, Seoul National University College of MedicineAbstract Cell-to-cell propagation of α-synuclein is thought to be the underlying mechanism of Parkinson’s disease progression. Recent evidence suggests that inflammation plays an important role in the propagation of protein aggregates. However, the mechanism by which inflammation regulates the propagation of aggregates remains unknown. Here, using in vitro cultures, we found that soluble factors secreted from activated microglia promote cell-to-cell propagation of α-synuclein and further showed that among these soluble factors, TNF-α had the most robust stimulatory activity. Treatment of neurons with TNF-α triggered cellular senescence, as shown by transcriptomic analyses demonstrating induction of senescence-associated genes and immunoanalysis of senescence phenotype marker proteins. Interestingly, secretion of α-synuclein was increased in senescent neurons, reflecting acquisition of a senescence-associated secretory phenotype (SASP). Using vacuolin-1, an inhibitor of lysosomal exocytosis, and RNAi against rab27a, we demonstrated that the SASP was mediated by lysosomal exocytosis. Correlative light and electron microscopy and immunoelectron microscopy confirmed that propagating α-synuclein aggregates were present in electron-dense lysosome-like compartments. TNF-α promoted the SASP through stimulation of lysosomal exocytosis, thereby increasing the secretion of α-synuclein. Collectively, these results suggest that TNF-α is the major inflammatory factor that drives cell-to-cell propagation of α-synuclein by promoting the SASP and subsequent secretion of α-synuclein.https://doi.org/10.1038/s12276-022-00789-x |
| spellingShingle | Eun-Jin Bae Minsun Choi Jeong Tae Kim Dong-Kyu Kim Min Kyo Jung Changyoun Kim Tae-Kyung Kim Jun Sung Lee Byung Chul Jung Soo Jean Shin Ka Hyun Rhee Seung-Jae Lee TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis Experimental and Molecular Medicine |
| title | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
| title_full | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
| title_fullStr | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
| title_full_unstemmed | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
| title_short | TNF-α promotes α-synuclein propagation through stimulation of senescence-associated lysosomal exocytosis |
| title_sort | tnf α promotes α synuclein propagation through stimulation of senescence associated lysosomal exocytosis |
| url | https://doi.org/10.1038/s12276-022-00789-x |
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