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FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment
Xingzong Sun1, Menghan Qian1, Hongliang Li1
1School of Medicine, Yunnan University, Kunming, 650091, China.
Abstract:
Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS) that is characterized by myelin damage, followed by axonal and ultimately neuronal loss, which has been found to be associated with mitophagy. The etiology and pathology of MS remain elusive. However, the role of FK506 binding protein 5 (FKBP5, also called FKBP51), a newly identified gene associated with MS, in the progression of the disease has not been well defined. Here, we observed that the progress of myelin loss and regeneration in Fkbp5ko mice treated with demyelination for the same amount of time was significantly slower than that in wild-type mice, and that mitophagy plays an important regulatory role in this process. To investigate the mechanism, we discovered that the levels of FKBP5 protein were greatly enhanced in the CNS of cuprizone (CPZ) mice and the myelin-denuded environment stimulates significant activation of the PINK1/Parkin-mediated mitophagy, in which the important regulator, PPAR-γ, is critically regulated by FKBP5. This study reveals the role of FKBP5 in regulating a dynamic pathway of natural restorative regulation of mitophagy through PPAR-γ in pathological demyelinating settings, which may provide potential targets for the treatment of demyelinating diseases.
Insights
FK506 binding protein 5 (FKBP5) influences myelin repair in multiple sclerosis models. This study shows FKBP5 regulates mitophagy via PPAR-γ, offering potential therapeutic targets for demyelinating diseases.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Multiple sclerosis (MS) is a CNS autoimmune and neurodegenerative disease characterized by myelin damage and neuronal loss.
- Mitophagy is implicated in MS pathology, but the role of FK506 binding protein 5 (FKBP5) remains unclear.
- FKBP5 is a newly identified gene associated with MS.
Purpose of the Study:
- To investigate the role of FKBP5 in the progression of demyelinating diseases, specifically its impact on myelin loss and regeneration.
- To elucidate the underlying molecular mechanisms, including the involvement of mitophagy and its regulators.
Main Methods:
- Utilized Fkbp5 knockout (Fkbp5ko) mice and cuprizone (CPZ)-induced demyelination model.
- Assessed myelin loss and regeneration rates in wild-type and Fkbp5ko mice.
- Investigated the activation of PINK1/Parkin-mediated mitophagy and the regulation of PPAR-γ by FKBP5 in the CNS.
Main Results:
- Fkbp5ko mice exhibited significantly slower myelin loss and regeneration compared to wild-type mice.
- FKBP5 protein levels were elevated in the CNS of CPZ-treated mice.
- A myelin-denuded environment activated PINK1/Parkin-mediated mitophagy, with FKBP5 critically regulating PPAR-γ.
Conclusions:
- FKBP5 plays a significant role in regulating the natural restorative pathway of mitophagy through PPAR-γ in pathological demyelinating conditions.
- This mechanism highlights FKBP5's involvement in myelin repair and suggests it as a potential therapeutic target for demyelinating diseases like MS.
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