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AIF3 splicing switch triggers neurodegeneration.
- Source :
-
Molecular neurodegeneration [Mol Neurodegener] 2021 Apr 14; Vol. 16 (1), pp. 25. Date of Electronic Publication: 2021 Apr 14. - Publication Year :
- 2021
-
Abstract
- Background: Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain.<br />Methods: AIF splicing induction in brain was determined by multiple approaches including 5' RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration.<br />Results: We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2-4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice.<br />Conclusions: We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.
- Subjects :
- Adolescent
Adult
Aged
Amino Acid Sequence
Animals
Apoptosis Inducing Factor deficiency
Apoptosis Inducing Factor genetics
Cells, Cultured
Child
Disease Models, Animal
Exons genetics
Female
Frontal Lobe chemistry
Gain of Function Mutation
Gene Editing
Gene Knock-In Techniques
Humans
Infant
Infant, Newborn
Infarction, Middle Cerebral Artery genetics
Infarction, Middle Cerebral Artery metabolism
Loss of Function Mutation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Mutant Strains
Middle Aged
Neurons metabolism
Oxidation-Reduction
Oxygen Consumption
Protein Isoforms genetics
Protein Isoforms physiology
Alternative Splicing
Apoptosis Inducing Factor physiology
Mitochondria metabolism
Nerve Degeneration genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1750-1326
- Volume :
- 16
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Molecular neurodegeneration
- Publication Type :
- Academic Journal
- Accession number :
- 33853653
- Full Text :
- https://doi.org/10.1186/s13024-021-00442-7