Spatial sequestration of misfolded proteins in neurodegenerative diseases

Properly folded, functional proteins are essential for cell health. Cells sustain protein homeostasis, or proteostasis, via protein quality control (PQC) mechanisms. It is currently hypothesized that a breakdown in proteostasis during ageing leads to the accumulation of protein aggregates in the cell and disease. Sequestration of misfolded proteins into PQC compartments represents one branch of the PQC network. In neurodegenerative diseases, certain proteins form abnormal protein deposits. Which PQC compartments house misfolded proteins associated with neurodegenerative diseases is still being investigated. It remains unclear if sequestration of these misfolded proteins is toxic or protective to the cell. Here, we review the current knowledge on various PQC compartments that form in the cell, the kinds of protein aggregates found in neurodegenerative diseases, and what is known about their sequestration. Understanding how protein sequestration occurs can shed light on why aggregates are toxic to the cell and are linked to neurodegenerative diseases like Huntington's, Alzheimer's, and Parkinson's diseases.