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PRAS40 alleviates neurotoxic prion peptide-induced apoptosis via mTOR-AKT signaling
Wei Yang1,2, Li-Feng Yang1, Zhi-Qi Song1
1National Animal Transmissible Spongiform Encephalopathy Laboratory and Key Laboratory of Animal Epidemiology and Zoonosis of Ministry of Agriculture, College of Veterinary Medicine and State Key Laboratory of Agrobiotechnology, China Agricultural University, Beijing, China.
Aims:
The proline-rich Akt substrate of 40-kDa (PRAS40) protein is a direct inhibitor of mTORC1 and an interactive linker between the Akt and mTOR pathways. The mammalian target of rapamycin (mTOR) is considered to be a central regulator of cell growth and metabolism. Several investigations have demonstrated that abnormal mTOR activity may contribute to the pathogenesis of several neurodegenerative disorders and lead to cognitive deficits.
Methods:
Here, we used the PrP peptide 106-126 (PrP106-126 ) in a cell model of prion diseases (also known as transmissible spongiform encephalopathies, TSEs) to investigate the mechanisms of mTOR-mediated cell death in prion diseases.
Results:
We have shown that, upon stress caused by PrP106-126 , the mTOR pathway activates and contributes to cellular apoptosis. Moreover, we demonstrated that PRAS40 down-regulates mTOR hyperactivity under stress conditions and alleviates neurotoxic prion peptide-induced apoptosis. The effect of PRAS40 on apoptosis is likely due to an mTOR/Akt signaling.
Conclusion:
PRAS40 inhibits mTORC1 hyperactivation and plays a key role in protecting cells against neurotoxic prion peptide-induced apoptosis. Thus, PRAS40 is a potential therapeutic target for prion disease.
Insights
Proline-rich Akt substrate of 40-kDa (PRAS40) inhibits mTORC1 hyperactivity, protecting cells from prion peptide-induced apoptosis. PRAS40 is a potential therapeutic target for neurodegenerative prion diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- The mammalian target of rapamycin (mTOR) pathway regulates cell growth and metabolism.
- Aberrant mTOR activity is implicated in neurodegenerative disorders and cognitive deficits.
- Proline-rich Akt substrate of 40-kDa (PRAS40) directly inhibits mTORC1 and links Akt and mTOR signaling.
Purpose of the Study:
- Investigate mTOR-mediated cell death mechanisms in prion diseases.
- Examine the role of PRAS40 in prion disease-induced neurotoxicity.
- Determine the therapeutic potential of PRAS40 in prion diseases.
Main Methods:
- Utilized a cell model of prion diseases using the PrP peptide 106-126 (PrP106-126).
- Assessed mTOR pathway activation and apoptosis induction under stress conditions.
- Evaluated the effect of PRAS40 on mTOR hyperactivity and apoptosis.
Main Results:
- Prion peptide 106-126 stress activates the mTOR pathway, contributing to cellular apoptosis.
- PRAS40 down-regulates mTOR hyperactivity under stress.
- PRAS40 alleviates neurotoxic prion peptide-induced apoptosis, likely via mTOR/Akt signaling.
Conclusions:
- PRAS40 inhibits mTORC1 hyperactivation, protecting cells from prion peptide-induced apoptosis.
- PRAS40 plays a crucial role in cellular defense against prion neurotoxicity.
- PRAS40 represents a promising therapeutic target for prion diseases.
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