<i>TOMM40</i> Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease
Translocase of outer mitochondrial membrane 40 (<i>TOMM40</i>) is located in the outer membrane of mitochondria. <i>TOMM40</i> is essential for protein import into mitochondria. <i>TOMM40</i> genetic variants are believed to increase the risk of Alzheimer’s diseas...
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MDPI AG
2023-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/4/4085 |
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| author | Yi-Chun Chen Shih-Cheng Chang Yun-Shien Lee Wei-Min Ho Yu-Hua Huang Yah-Yuan Wu Yi-Chuan Chu Kuan-Hsuan Wu Li-Shan Wei Hung-Li Wang Ching-Chi Chiu |
| author_facet | Yi-Chun Chen Shih-Cheng Chang Yun-Shien Lee Wei-Min Ho Yu-Hua Huang Yah-Yuan Wu Yi-Chuan Chu Kuan-Hsuan Wu Li-Shan Wei Hung-Li Wang Ching-Chi Chiu |
| author_sort | Yi-Chun Chen |
| collection | DOAJ |
| description | Translocase of outer mitochondrial membrane 40 (<i>TOMM40</i>) is located in the outer membrane of mitochondria. <i>TOMM40</i> is essential for protein import into mitochondria. <i>TOMM40</i> genetic variants are believed to increase the risk of Alzheimer’s disease (AD) in different populations. In this study, three exonic variants (rs772262361, rs157581, and rs11556505) and three intronic variants (rs157582, rs184017, and rs2075650) of the <i>TOMM40</i> gene were identified from Taiwanese AD patients using next-generation sequencing. Associations between the three <i>TOMM40</i> exonic variants and AD susceptibility were further evaluated in another AD cohort. Our results showed that rs157581 (c.339T > C, p.Phe113Leu, F113L) and rs11556505 (c.393C > T, p.Phe131Leu, F131L) were associated with an increased risk of AD. We further utilized cell models to examine the role of TOMM40 variation in mitochondrial dysfunction that causes microglial activation and neuroinflammation. When expressed in BV2 microglial cells, the AD-associated mutant (F113L) or (F131L) TOMM40 induced mitochondrial dysfunction and oxidative stress-induced activation of microglia and NLRP3 inflammasome. Pro-inflammatory TNF-α, IL-1β, and IL-6 released by mutant (F113L) or (F131L) TOMM40-activated BV2 microglial cells caused cell death of hippocampal neurons. Taiwanese AD patients carrying TOMM40 missense (F113L) or (F131L) variants displayed an increased plasma level of inflammatory cytokines IL-6, IL-18, IL-33, and COX-2. Our results provide evidence that TOMM40 exonic variants, including rs157581 (F113L) and rs11556505 (F131L), increase the AD risk of the Taiwanese population. Further studies suggest that AD-associated mutant (F113L) or (F131L) TOMM40 cause the neurotoxicity of hippocampal neurons by inducing the activation of microglia and NLRP3 inflammasome and the release of pro-inflammatory cytokines. |
| first_indexed | 2024-03-11T08:41:07Z |
| format | Article |
| id | doaj.art-b71347c236f64aa0951459fe413ef535 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T08:41:07Z |
| publishDate | 2023-02-01 |
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| spelling | doaj.art-b71347c236f64aa0951459fe413ef5352023-11-16T21:09:16ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-02-01244408510.3390/ijms24044085<i>TOMM40</i> Genetic Variants Cause Neuroinflammation in Alzheimer’s DiseaseYi-Chun Chen0Shih-Cheng Chang1Yun-Shien Lee2Wei-Min Ho3Yu-Hua Huang4Yah-Yuan Wu5Yi-Chuan Chu6Kuan-Hsuan Wu7Li-Shan Wei8Hung-Li Wang9Ching-Chi Chiu10Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center, College of Medicine, Chang Gung University, Taoyuan 33302, TaiwanDepartment of Laboratory Medicine, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan 33305, TaiwanDepartment of Biotechnology, Ming Chuan University, Taoyuan 33348, TaiwanDepartment of Neurology, Chang Gung Memorial Hospital Linkou Medical Center, College of Medicine, Chang Gung University, Taoyuan 33302, TaiwanDepartment of Neurology, Chang Gung Memorial Hospital Linkou Medical Center, College of Medicine, Chang Gung University, Taoyuan 33302, TaiwanDepartment of Neurology, Chang Gung Memorial Hospital Linkou Medical Center, College of Medicine, Chang Gung University, Taoyuan 33302, TaiwanDepartment of Neurology, Chang Gung Memorial Hospital Linkou Medical Center, College of Medicine, Chang Gung University, Taoyuan 33302, TaiwanDepartment of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan 33302, TaiwanDepartment of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan 33302, TaiwanNeuroscience Research Center, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, TaiwanDepartment of Laboratory Medicine, Chang Gung Memorial Hospital Linkou Medical Center, Taoyuan 33305, TaiwanTranslocase of outer mitochondrial membrane 40 (<i>TOMM40</i>) is located in the outer membrane of mitochondria. <i>TOMM40</i> is essential for protein import into mitochondria. <i>TOMM40</i> genetic variants are believed to increase the risk of Alzheimer’s disease (AD) in different populations. In this study, three exonic variants (rs772262361, rs157581, and rs11556505) and three intronic variants (rs157582, rs184017, and rs2075650) of the <i>TOMM40</i> gene were identified from Taiwanese AD patients using next-generation sequencing. Associations between the three <i>TOMM40</i> exonic variants and AD susceptibility were further evaluated in another AD cohort. Our results showed that rs157581 (c.339T > C, p.Phe113Leu, F113L) and rs11556505 (c.393C > T, p.Phe131Leu, F131L) were associated with an increased risk of AD. We further utilized cell models to examine the role of TOMM40 variation in mitochondrial dysfunction that causes microglial activation and neuroinflammation. When expressed in BV2 microglial cells, the AD-associated mutant (F113L) or (F131L) TOMM40 induced mitochondrial dysfunction and oxidative stress-induced activation of microglia and NLRP3 inflammasome. Pro-inflammatory TNF-α, IL-1β, and IL-6 released by mutant (F113L) or (F131L) TOMM40-activated BV2 microglial cells caused cell death of hippocampal neurons. Taiwanese AD patients carrying TOMM40 missense (F113L) or (F131L) variants displayed an increased plasma level of inflammatory cytokines IL-6, IL-18, IL-33, and COX-2. Our results provide evidence that TOMM40 exonic variants, including rs157581 (F113L) and rs11556505 (F131L), increase the AD risk of the Taiwanese population. Further studies suggest that AD-associated mutant (F113L) or (F131L) TOMM40 cause the neurotoxicity of hippocampal neurons by inducing the activation of microglia and NLRP3 inflammasome and the release of pro-inflammatory cytokines.https://www.mdpi.com/1422-0067/24/4/4085Alzheimer’s diseaseTOMM40SNPmicroglianeuroinflammationNLRP3 |
| spellingShingle | Yi-Chun Chen Shih-Cheng Chang Yun-Shien Lee Wei-Min Ho Yu-Hua Huang Yah-Yuan Wu Yi-Chuan Chu Kuan-Hsuan Wu Li-Shan Wei Hung-Li Wang Ching-Chi Chiu <i>TOMM40</i> Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease International Journal of Molecular Sciences Alzheimer’s disease TOMM40 SNP microglia neuroinflammation NLRP3 |
| title | <i>TOMM40</i> Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease |
| title_full | <i>TOMM40</i> Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease |
| title_fullStr | <i>TOMM40</i> Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease |
| title_full_unstemmed | <i>TOMM40</i> Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease |
| title_short | <i>TOMM40</i> Genetic Variants Cause Neuroinflammation in Alzheimer’s Disease |
| title_sort | i tomm40 i genetic variants cause neuroinflammation in alzheimer s disease |
| topic | Alzheimer’s disease TOMM40 SNP microglia neuroinflammation NLRP3 |
| url | https://www.mdpi.com/1422-0067/24/4/4085 |
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