Page 70 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-38]

Novel neuroprotective agent regulates Tau proteostasis via

stress-responsive activation of PERK signaling

Hana Cho¹˙#, Young-Hee Shin²˙#, Bo Young Choi³, Jaeyoung Ha¹, Jonghoon Kim⁴, Seung Bum Park¹˙²˙*

¹Department of Biophysics and Chemical Biology, Seoul National University, Seoul 08826, South Korea,

²Department of Chemistry, Seoul National University, Seoul 08826, South Korea, ³Department of Physiology,
College of Medicine, Hallym University, Chuncheon 24252, South Korea, ⁴Department of Chemistry, Soongsil

University, Seoul 06978, South Korea

The deposition of specific protein aggregates is the well-known risk factor for neurodegenerative diseases,

representing the impairment of neuronal proteostasis. Here, we aimed to explore SB1617 mode of action, discovered
among our in-house library to effectively suppress tau protein aggregation. We revealed that SB1617 transiently
enhances and prolongs Protein kinase-like Endoplasmic Reticulum Kinase (PERK) signaling, one of ER stress sensor

proteins, under cell stressed condition. Subsequently, SB1617 phosphorylates eIF2alpha and sustains its modification,
resulting in inhibition of global protein synthesis to recover cellular homeostasis. Besides, by administration of

SB1617 along with translation or autophagy inhibitors, we verified that SB1617 regulates the Tau homeostasis via
both translation and autophagy pathway. Also, SB1617 shows beneficial effects on neuroprotection and motor

neuronal behaviors in Traumatic Brain Injury (TBI) mice model. Accordingly, the proteostasis regulation via PERK
signaling could open new avenues of investigation in tauopathies and lead to a better understanding of other

proteinopathies and potentially help with the development of new therapeutic approaches.