The endoplasmic reticulum (ER) is the key cellular organelle responsible for the post-translational folding of proteins into their bioactive conformation, and the maintenance of proper proteome folding by certain quality control mechanisms (known as proteostasis). Overloaded or impaired proteostasis can cause cellular accumulation and aggregation of malfunctioned unfolded proteins, which have been associated with many neurodegenerative diseases.1 Therefore, fluorescently labelled compounds capable of assessing the proteostasis efficiency may not only provide valuable information on ER activities, but also become clinically useful tools to assist in early disease diagnosis and disease progression monitoring.
The abundancy of unfolded proteins in the ER lumen is a direct indicator of the proteostasis efficiency. A common feature of such proteins is that their cysteine residues, the most buried amino acid residue in normal proteins, become exposed to the cellular environment. In this regard, fluorogens with high reactivity towards the thiol groups on exposed cysteine residues will enable convenient assessment of proteostasis integrity via measuring the fluorescent intensity.2
Based on the well-documented aggregation-induced emission (AIE) active fluorogen tetraphenylethene (TPE),3 we report our work on the design, synthesis and spectral analysis of a novel fluorogen. Notably, AIE-active fluorogens become progressively emissive upon forming aggregates, in contrast to those traditional fluorogens that show quenched emission. This unique feature makes AIE-active fluorogens highly preferential in assessing protein aggregation. This fluorogen exhibited turn-on fluorescence in the presence of unfolded proteins, as well as cell penetration, selective ER localisation, and intensified emission in stressed Neuro-2a cells.
References
1 Narayan, P., Ehsani, S. & Lindquist, S. Nat. Chem. Biol. 10, 911 (2014).
2 Chen, M. Z. et al. Nat. Commun. 8, 474 (2017).
3 Hong, Y., Lam, J. W. Y. & Tang, B. Z. Chem. Soc. Rev. 40, 5361 (2011).