Several proteolytic systems including ubiquitin (Ub)-proteasome system (UPS), chaperonemediated
autophagy (CMA), and macroautophagy are used by the mammalian cells to remove misfolded
proteins (MPs). UPS mediates degradation of most of the MPs, where Ub-conjugated substrates are deubiquitinated,
unfolded, and passed through the proteasome’s narrow chamber, and eventually break into
smaller peptides. It has been observed that the substrates that show a specific degradation signal, the
KFERQ sequence motif, can be delivered to and go through CMA-mediated degradation in lysosomes.
Macroautophagy can help in the degradation of substrates that are prone to aggregation and resistant to
both the CMA and UPS. In the aforesaid case, cargoes are separated into autophagosomes before
lysosomal hydrolase-mediated degradation. Even though the majority of the aggregated and MPs in the
human proteome can be removed via cellular protein quality control (PQC), some mutant and native
proteins tend to aggregate into β-sheet-rich oligomers that exhibit resistance to all identified proteolytic
processes and can, therefore, grow into extracellular plaques or inclusion bodies. Indeed, the buildup of
protease-resistant aggregated and MPs is a usual process underlying various protein misfolding disorders,
including neurodegenerative diseases (NDs) for example Alzheimer’s disease, Parkinson’s disease,
Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. In this article, we have focused
on the contribution of PQC in the degradation of pathogenic proteins in NDs.