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A Novel Role for BRIP1/FANCJ in Neuronal Cells Health and in Resolving Oxidative Stress-Induced DNA Lesions
- Source :
- Journal of Alzheimer's disease : JAD. 85(1)
- Publication Year :
- 2021
-
Abstract
- Background: DNA damage accumulation and mitochondrial abnormalities are elevated in neurons during aging and may contribute to neurodegenerative pathologic conditions such as Alzheimer’s disease. BRCA1 interacting protein 1 or BRIP1 is a 5’ to 3’ DNA helicase that catalyzes many abnormal DNA structures during DNA replication, gene transcription, and recombination, and contribute to genomic integrity. Objective: BRIP1 functions were reasonably well studied in DNA repair; however, there is limited data on its role and regulation during aging and neurodegenerative diseases. Methods: We used immunohistochemistry, western blot, and qRT-PCR assays to analyze the expression of BRIP1. Immunofluorescence studies were performed to study the formation of R-loops, reactive oxygen species (ROS) generation, and mitochondrial morphology. Flow cytometry and transmission electron microscopy were used to evaluate mitochondrial ROS and mitochondrial structures, respectively. Oxygen consumption rate was measured using Seahorse, and the Presto Blue™ assays were used to evaluate cell viability. Results: Our results demonstrate the expression of BRIP1 in mouse and human brain tissues and in neuronal cell lines. BRIP1 levels were elevated in the hippocampal regions of the brains, specifically in the dentate gyrus. BRIP1 downregulation in neuronal cells caused increased R-loop formation basally and in response to H2O2 treatment. Furthermore, BRIP1 deficient cells exhibited elevated levels of excitotoxicity induced by L-Glutamic acid exposure as evidenced by (mitochondrial) ROS levels, deteriorated mitochondrial health, and cell death compared to BRIP1 proficient neuronal cells. Conclusion: Overall, our results indicate an important role for BRIP1 in maintaining neuronal cell health and homeostasis by suppressing cellular oxidative stress.
- Subjects :
- Mitochondrial ROS
Programmed cell death
DNA damage
DNA repair
Cell Survival
Cell
Excitotoxicity
medicine.disease_cause
Cell Line
Mice
medicine
Animals
Humans
Neurons
Chemistry
General Neuroscience
DNA replication
Brain
Neurodegenerative Diseases
General Medicine
Fanconi Anemia Complementation Group Proteins
Cell biology
Mice, Inbred C57BL
Psychiatry and Mental health
Clinical Psychology
Oxidative Stress
medicine.anatomical_structure
Geriatrics and Gerontology
Oxidative stress
RNA Helicases
DNA Damage
Subjects
Details
- ISSN :
- 18758908
- Volume :
- 85
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Alzheimer's disease : JAD
- Accession number :
- edsair.doi.dedup.....8b90f54afb16cdcf5b1ab37641cca302