AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression
Abstract Background Leucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease (PD). Especially, LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD. Advanced glycation en...
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| Format: | Article |
| Language: | English |
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BMC
2018-01-01
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| Series: | Translational Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40035-018-0106-z |
| _version_ | 1819154292946239488 |
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| author | Hyun Jin Cho Chengsong Xie Huaibin Cai |
| author_facet | Hyun Jin Cho Chengsong Xie Huaibin Cai |
| author_sort | Hyun Jin Cho |
| collection | DOAJ |
| description | Abstract Background Leucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease (PD). Especially, LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD. Advanced glycation end products (AGEs) are produced in high amounts in diabetes and diverse aging-related disorders, such as cardiovascular disease, renal disease, and neurological disease. AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death. RAGE, receptor of AGEs, is activated by interaction with AGEs and mediates AGE-induced cytotoxicity. Whether AGE and RAGE are involved in the pathogenesis of mutant LRRK2 is unknown. Methods Using cell lines transfected with mutant LRRK2 as well as primary neuronal cultures derived from LRRK2 wild-type (WT) and G2019S transgenic mice, we compared the impact of AGE treatment on the survival of control and mutant cells by immunostaining. We also examined the levels of RAGE proteins in the brains of transgenic mice and PD patients by western blots. Results We show that LRRK2 G2019S mutant-expressing neurons were more sensitive to AGE-induced cell death compared to controls. Furthermore, we found that the levels of RAGE proteins were upregulated in LRRK2 G2019S mutant cells. Conclusions These data suggest that enhanced AGE-RAGE interaction contributes to LRRK2 G2019S mutation-mediated progressive neuronal loss in PD. |
| first_indexed | 2024-12-22T15:18:46Z |
| format | Article |
| id | doaj.art-0f524fcb4d994d38a23b0c869666abb2 |
| institution | Directory Open Access Journal |
| issn | 2047-9158 |
| language | English |
| last_indexed | 2024-12-22T15:18:46Z |
| publishDate | 2018-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Translational Neurodegeneration |
| spelling | doaj.art-0f524fcb4d994d38a23b0c869666abb22022-12-21T18:21:41ZengBMCTranslational Neurodegeneration2047-91582018-01-01711810.1186/s40035-018-0106-zAGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expressionHyun Jin Cho0Chengsong Xie1Huaibin Cai2Department of Biochemistry and Biomedical Sciences, Seoul National University, College of MedicineTransgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthTransgenics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthAbstract Background Leucine-rich repeat kinase 2 (LRRK2) mutations represent the most common genetic cause of sporadic and familial Parkinson’s disease (PD). Especially, LRRK2 G2019S missense mutation has been identified as the most prevalent genetic cause in the late-onset PD. Advanced glycation end products (AGEs) are produced in high amounts in diabetes and diverse aging-related disorders, such as cardiovascular disease, renal disease, and neurological disease. AGEs trigger intracellular signaling pathway associated with oxidative stress and inflammation as well as cell death. RAGE, receptor of AGEs, is activated by interaction with AGEs and mediates AGE-induced cytotoxicity. Whether AGE and RAGE are involved in the pathogenesis of mutant LRRK2 is unknown. Methods Using cell lines transfected with mutant LRRK2 as well as primary neuronal cultures derived from LRRK2 wild-type (WT) and G2019S transgenic mice, we compared the impact of AGE treatment on the survival of control and mutant cells by immunostaining. We also examined the levels of RAGE proteins in the brains of transgenic mice and PD patients by western blots. Results We show that LRRK2 G2019S mutant-expressing neurons were more sensitive to AGE-induced cell death compared to controls. Furthermore, we found that the levels of RAGE proteins were upregulated in LRRK2 G2019S mutant cells. Conclusions These data suggest that enhanced AGE-RAGE interaction contributes to LRRK2 G2019S mutation-mediated progressive neuronal loss in PD.http://link.springer.com/article/10.1186/s40035-018-0106-zParkinson’s diseaseLRRK2G2019SAGERAGENeuronal death |
| spellingShingle | Hyun Jin Cho Chengsong Xie Huaibin Cai AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression Translational Neurodegeneration Parkinson’s disease LRRK2 G2019S AGE RAGE Neuronal death |
| title | AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression |
| title_full | AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression |
| title_fullStr | AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression |
| title_full_unstemmed | AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression |
| title_short | AGE-induced neuronal cell death is enhanced in G2019S LRRK2 mutation with increased RAGE expression |
| title_sort | age induced neuronal cell death is enhanced in g2019s lrrk2 mutation with increased rage expression |
| topic | Parkinson’s disease LRRK2 G2019S AGE RAGE Neuronal death |
| url | http://link.springer.com/article/10.1186/s40035-018-0106-z |
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