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Decrease of neuronal FKBP4/FKBP52 modulates perinuclear lysosomal positioning and MAPT/Tau behavior during
Béatrice Chambraud1, Corentin Daguinot1, Kevin Guillemeau1
1INSERM U1195, Université Paris-Saclay, Kremlin-Bicêtre, France.
Autophagy
|January 18, 2021
Summary
FKBP4 decrease in Alzheimer disease (AD) neurons impairs autophagy and increases tau (MAPT) secretion and accumulation. Restoring FKBP4 may help manage tauopathy progression.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Defects in autophagy-lysosomal protein degradation are implicated in neurodegenerative diseases like Alzheimer disease (AD).
- Accumulation of aggregation-prone proteins, such as microtubule-associated protein tau (MAPT), is a hallmark of AD.
- FKBP4/FKBP52 was previously localized in the lysosomal system of healthy neurons, suggesting a role in lysosome function.
Purpose of the Study:
- To investigate the role of FKBP4 in the autophagy-lysosomal system under proteotoxic stress conditions induced by MAPT.
- To determine the impact of FKBP4 decrease on MAPT accumulation, secretion, and autophagy in neuronal models.
- To explore the potential of FKBP4 in modulating MAPT pathogenesis in the context of tauopathy.
Main Methods:
- Utilized human neuroblastoma (SH-SY5Y) cell lines and dorsal root ganglion (DRG) neurons from MAPT P301S transgenic mice.
- Induced proteotoxic stress using MAPT accumulation and manipulated FKBP4 levels via knockdown (shRNA) and overexpression.
- Assessed autophagy-lysosomal system function, MAPT and MAP1LC3/LC3 localization, clustering, secretion, and expression levels.
Main Results:
- FKBP4 decrease in SH-SY5Y cells and mouse DRG neurons impaired autophagy-lysosomal function under MAPT-induced stress.
- MAPT accumulation led to lysosomal clustering and FKBP4 recruitment, with FKBP4 decrease altering this process and increasing MAPT/MAP1LC3 secretion.
- Ectopic FKBP4 expression prevented MAPT secretion, and FKBP4 deficiency reduced MAP1LC3-II and increased MAPT accumulation during long-term stress.
Conclusions:
- FKBP4 plays a crucial role in regulating the autophagy-lysosomal system's response to MAPT-induced proteotoxic stress.
- Reduced FKBP4 levels in AD neurons may contribute to tauopathy by impairing autophagy efficiency and modulating MAPT secretion and accumulation.
- FKBP4 modulation presents a potential therapeutic target for neurodegenerative diseases characterized by tau pathology.
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