Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation

Area of Science:

• Molecular Biology
• Cellular Biology
• Neuroscience

Background:

• Endoplasmic reticulum (ER) proteostasis imbalances are implicated in various degenerative diseases.
• These diseases are often linked to extracellular protein misfolding and aggregation.
• Genetic activation of the Unfolded Protein Response (UPR) transcription factor ATF6 can mitigate these issues.

Purpose of the Study:

• To identify non-toxic small molecules that mimic ATF6-mediated ER proteostasis reprogramming.
• To investigate if these molecules can reduce the secretion and aggregation of amyloidogenic proteins.

Main Methods:

• Screening for small molecules using UPR reporters and transcriptional profiling.
• Assessing molecule-induced ER reprogramming independent of global ER stress.
• Evaluating the effect of molecules on amyloidogenic protein secretion and aggregation.

Main Results:

• Identified small molecules that activate endogenous ATF6, reprogramming ER proteostasis.
• Demonstrated that this reprogramming occurs independently of global ER stress.
• Showed that these molecules selectively reduce the secretion and extracellular aggregation of amyloidogenic proteins.

Conclusions:

• Small molecule-driven ER reprogramming via ATF6 activation is a viable therapeutic strategy.
• This approach shows promise for ameliorating ER dysfunction in degenerative protein aggregation diseases.