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ORP150-CHIP chaperone antagonism control BACE1-mediated amyloid processing.

Neha Chanana¹, Uttam Pati¹

¹School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.

Journal of Cellular Biochemistry

|December 22, 2017

Summary

Researchers found that ER chaperone ORP150 and cellular chaperone CHIP antagonistically control BACE1 and Aβ42, key factors in Alzheimer's disease progression. This discovery offers new therapeutic strategies targeting chaperone interactions to prevent amyloid plaque formation.

Keywords:

Aβ42 BACE1 CHIP ORP150 chaperones

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Area of Science:

Neuroscience
Molecular Biology
Cellular Biology

Background:

Alzheimer's disease (AD) is characterized by amyloid plaques, primarily composed of amyloid-beta 42 (Aβ42).
BACE1 (Beta-site amyloid precursor protein cleaving enzyme 1) is a crucial enzyme initiating Aβ42 generation.
The influence of chaperone proteins on BACE1 activity and Aβ42 production remains largely unexplored.

Purpose of the Study:

To investigate the role of chaperone synergy and antagonism in BACE1-mediated amyloid processing.
To elucidate the interaction between the ER chaperone ORP150 and the cellular chaperone CHIP in regulating BACE1 levels and Aβ42 generation.

Main Methods:

Post-translational modification analysis of BACE1.
Investigating the interaction between ORP150, CHIP, and BACE1.
Utilizing siRNA (small interfering RNA) to reduce ORP150 levels (siORP150).
Assessing BACE1 degradation and Aβ42 generation under varying chaperone conditions.

Main Results:

ORP150 interacts with and stabilizes BACE1 at the post-translational level, enhancing BACE1 activity and Aβ42 production.
ORP150 masks the degradation of BACE1 mediated by CHIP.
Reduction of ORP150 (siORP150) reverses its stabilizing effect, leading to increased BACE1 degradation.
ORP150 and CHIP exhibit antagonistic regulation of BACE1 levels under both normal and stress conditions.

Conclusions:

A novel phenomenon of chaperone antagonism regulating BACE1-mediated Aβ42 generation has been identified.
ORP150 and CHIP inversely control BACE1 levels through their opposing chaperone activities.
Targeting the suppression of ORP150 and activation of CHIP's E3-ligase activity presents a potential therapeutic strategy for Alzheimer's disease by preventing Aβ42 generation.