Scientists have identified, a protein of the endoplasmic reticulum, as a potential game-changer in the management of prion diseases, a class of incurable and deadly neurodegenerative disorders. These diseases, which include Creutzfeldt-Jakob disease, are caused by the accumulation of misfolded prion proteins (PrPSc) that wreak havoc on the brain, triggering progressive neurological decline.
Researchers at the National Institute of Immunology in New Delhi show that ARL6IP5, an endoplasmic reticulum (ER) stress regulator, plays a crucial role in clearing these toxic aggregates of misfolded proteins. The study, published in Autophagy, highlights how ARL6IP5 activates a selective autophagy process called reticulophagy, targeting damaged ER regions for degradation and alleviating stress within the cell.
In prion-infected cell models, the overexpression of ARL6IP5 not only reduced the burden of prion proteins but also reversed disease-related cellular damage. This protective effect was achieved through the activation of calcium-dependent pathways and interactions with key proteins, such as the reticulophagy receptor CALCOCO1 and lysosomal protein LAMP1, which facilitate the breakdown of harmful aggregates.
“This discovery could pave the way for therapies targeting ARL6IP5 to manage prion diseases and possibly other protein misfolding disorders like Parkinson’s and Alzheimer’s,” says lead researcher Dr. Sarika Gupta. While still in the early stages, this breakthrough offers hope for tackling these devastating conditions, long deemed untreatable.
Reference
Kamble, K., Kumar, U., Aahra, H., Yadav, M., Bhola, S., & Gupta, S. (2024). A novel ER stress regulator ARL6IP5 induces reticulophagy to ameliorate the prion burden. Autophagy, 1–21. Advance online publication. https://doi.org/10.1080/15548627.2024.2410670