GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus
Background: Despite the availability of various antiepileptic treatments, approximately 30 % of epilepsy patients remain refractory to conventional therapies, underscoring the need for neuroprotective strategies. This study investigates the role of GrpEL1 in modulating the mitochondrial unfolded pro...
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Elsevier
2025-03-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000543 |
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| author | Minjia Xie Xin Wu Xi Liu Longyuan Li Feng Gu Xinyu Tao Bingyi Song Lei Bai Di Li Haitao Shen Zongqi Wang Wei Gao |
| author_facet | Minjia Xie Xin Wu Xi Liu Longyuan Li Feng Gu Xinyu Tao Bingyi Song Lei Bai Di Li Haitao Shen Zongqi Wang Wei Gao |
| author_sort | Minjia Xie |
| collection | DOAJ |
| description | Background: Despite the availability of various antiepileptic treatments, approximately 30 % of epilepsy patients remain refractory to conventional therapies, underscoring the need for neuroprotective strategies. This study investigates the role of GrpEL1 in modulating the mitochondrial unfolded protein response (UPRmt) and its potential protective effects on hippocampal neurons following experimental status epilepticus (SE). Methods: The effects of GrpEL1 were assessed in vivo using a Lithium-pilocarpine rat model of SE and in vitro with glutamate-treated HT22 hippocampal cells. Protein expression and interactions were analyzed by Western blot, immunofluorescence, and co-immunoprecipitation. Neuronal survival was evaluated through Nissl staining. Mitochondrial function was evaluated aggresome formation, mitochondrial membrane potential (MMP) assays, mitochondrial oxygen consumption rate (OCR) measurements, and behavioral assessments using the Morris water maze. Results: In the SE rat model, mtHSP70 levels were significantly upregulated in mitochondria, while GrpEL1 expression remained relatively stable. Overexpression of GrpEL1 led to a reduction in neuronal damage and improved functional recovery post-SE. In vitro, GrpEL1 overexpression enhanced the GrpEL1-mtHSP70 interaction, reduced the accumulation of misfolded proteins, and decreased neuronal apoptosis. Furthermore, GrpEL1 overexpression mitigated mitochondrial dysfunction by preserving MMP and improving mitochondrial bioenergetics, as evidenced by enhanced mitochondrial OCR. Conclusion: GrpEL1 plays a crucial role in maintaining mitochondrial proteostasis and mitigating hippocampal neuronal injury following SE by regulating UPRmt. These findings suggest that GrpEL1 may represent a promising target for therapeutic intervention to protect against seizure-induced neurodegeneration. |
| format | Article |
| id | doaj-art-377d735a5cd547b5b931adb005c4f8cd |
| institution | OA Journals |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-377d735a5cd547b5b931adb005c4f8cd2025-08-20T02:14:53ZengElsevierNeurobiology of Disease1095-953X2025-03-0120610683810.1016/j.nbd.2025.106838GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticusMinjia Xie0Xin Wu1Xi Liu2Longyuan Li3Feng Gu4Xinyu Tao5Bingyi Song6Lei Bai7Di Li8Haitao Shen9Zongqi Wang10Wei Gao11Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaDepartment of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaCorresponding authors at: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China.; Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaCorresponding authors at: Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006, China.; Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, ChinaBackground: Despite the availability of various antiepileptic treatments, approximately 30 % of epilepsy patients remain refractory to conventional therapies, underscoring the need for neuroprotective strategies. This study investigates the role of GrpEL1 in modulating the mitochondrial unfolded protein response (UPRmt) and its potential protective effects on hippocampal neurons following experimental status epilepticus (SE). Methods: The effects of GrpEL1 were assessed in vivo using a Lithium-pilocarpine rat model of SE and in vitro with glutamate-treated HT22 hippocampal cells. Protein expression and interactions were analyzed by Western blot, immunofluorescence, and co-immunoprecipitation. Neuronal survival was evaluated through Nissl staining. Mitochondrial function was evaluated aggresome formation, mitochondrial membrane potential (MMP) assays, mitochondrial oxygen consumption rate (OCR) measurements, and behavioral assessments using the Morris water maze. Results: In the SE rat model, mtHSP70 levels were significantly upregulated in mitochondria, while GrpEL1 expression remained relatively stable. Overexpression of GrpEL1 led to a reduction in neuronal damage and improved functional recovery post-SE. In vitro, GrpEL1 overexpression enhanced the GrpEL1-mtHSP70 interaction, reduced the accumulation of misfolded proteins, and decreased neuronal apoptosis. Furthermore, GrpEL1 overexpression mitigated mitochondrial dysfunction by preserving MMP and improving mitochondrial bioenergetics, as evidenced by enhanced mitochondrial OCR. Conclusion: GrpEL1 plays a crucial role in maintaining mitochondrial proteostasis and mitigating hippocampal neuronal injury following SE by regulating UPRmt. These findings suggest that GrpEL1 may represent a promising target for therapeutic intervention to protect against seizure-induced neurodegeneration.http://www.sciencedirect.com/science/article/pii/S0969996125000543GrpEL1Mitochondrial unfolded protein response (UPRmt)Status epilepticusHippocampal neuronsNeuronal protectionMitochondrial dysfunction |
| spellingShingle | Minjia Xie Xin Wu Xi Liu Longyuan Li Feng Gu Xinyu Tao Bingyi Song Lei Bai Di Li Haitao Shen Zongqi Wang Wei Gao GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus Neurobiology of Disease GrpEL1 Mitochondrial unfolded protein response (UPRmt) Status epilepticus Hippocampal neurons Neuronal protection Mitochondrial dysfunction |
| title | GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus |
| title_full | GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus |
| title_fullStr | GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus |
| title_full_unstemmed | GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus |
| title_short | GrpEL1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus |
| title_sort | grpel1 overexpression mitigates hippocampal neuron damage via mitochondrial unfolded protein response after experimental status epilepticus |
| topic | GrpEL1 Mitochondrial unfolded protein response (UPRmt) Status epilepticus Hippocampal neurons Neuronal protection Mitochondrial dysfunction |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000543 |
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