Development of ER-targeted therapeutics against protein aggregation diseases

2017 Fiscal Year Final Research Report

• Project/Area Number: 15K08404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: The University of Tokushima
• Principal Investigator: YAMAZAKI Tetsuo 徳島大学, 大学院医歯薬学研究部(薬学系), 教授 (90330208)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Keywords: 小胞体 / CLN6 / 凝集体

Outline of Final Research Achievements

The aim of this project is to develop therapeutic interventions against protein aggregation diseases. Mutations within the alphaB-crystallin (aBC) gene are linked to crystallinopathy, characterized by intracellular accumulation of protein aggregates. We previously demonstrated that enforced expression of aBC on the endoplasmic reticulum (ER) prevented aggregation of the R120G aBC mutant, suggesting that manipulation of the ER-anchored aBC (ERaBC) target is effective for protein aggregation diseases. In this study, CLN6, an ER transmembrane protein, was isolated as an ERaBC binder. We revealed that CLN6 not only mediates the anti-aggregate activity of ERaBC but also prevents the R120G mutant from aggregating independently of ERaBC. CLN6 profoundly inhibited aggregation of the ALS-associated TDP-43 variant as well. Overall, we conclude that dictating CLN6 would be a promising strategy for a wide array of protein aggregation diseases.

Free Research Field

病理学