Abstract
Cellular health depends on the integrity and functionality of the proteome. Each cell is equipped with a protein quality control machinery that maintains protein homeostasis (proteostasis) by helping proteins adopt and keep their native structure, and ensuring the degradation of damaged proteins. Postmitotic cells such as neurons are especially vulnerable to disturbances of proteostasis. Defects of protein quality control occur in aging and have been linked to several disorders, including neurodegenerative diseases. However, the exact nature and time course of such disturbances in the context of brain diseases remain poorly understood. Sensors that allow visualization and quantitative analysis of proteostasis capacity in neurons are essential for gaining a better understanding of disease mechanisms and for testing potential therapies. Here, I provide an overview of available biosensors for assessing the functionality of the neuronal proteostasis network, point out the advantages and limitations of different sensors, and outline their potential for biological discoveries and translational applications.
Highlights
Luciferase offers a second way of analyzing folding efficiency, as it displays reduced enzymatic activity when not folded properly. This can be detected by measuring bioluminescence emitted in a luciferase assay, providing a reliable quantitative readout with a large dynamic range. One of such sensors made up of the luciferase from the firefly Photinus pyralis fused to an enhanced green fluorescent protein (Fluc-EGFP, Figure 2C), is available as a series of progressively destabilized mutants (Gupta et al, 2011), which broaden the spectrum of proteostasis capacity states that can be probed
While the bioluminescence readout showed very high sensitivity in cell lines, it proved less sensitive in bulk brain tissue of proteinopathy model mice (Gupta et al, 2011; Blumenstock et al, 2021), possibly due to the heterogeneity of neuronal cell types that differ in their reactions to misfolding
The available toolbox of proteostasis biosensors has been quickly expanding during the last decade
Summary
Proteins have to be synthesized in required amounts, correctly folded and assembled into complexes, and turned over at appropriate rates. Proteostasis sensors are used to monitor the functional state of the protein quality control system in living cells and whole organisms.
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