Maintaining the intracellular and extracellular functional network of proteins is called proteostasis. The cellular stress-induced damage to proteins aggravates protein misfolding, ultimately overwhelming the degradation mechanism. Disturbances in protein homeostasis are prominent in age-related neurological conditions. In a mammalian cell system, misfolded proteins were removed utilizing multiple proteolytic systems. These systems include ubiquitin (Ub)–proteasome system (UPS), macroautophagy and chaperone-mediated autophagy (CMA). The UPS is principally responsible for the degradation of most misfolded proteins. At UPS, the substrate is Ub-conjugated then deubiquitinated and unfolded. The substrates that have a KFERQ sequence signal are degraded and delivered to lysosomes using CMA. The substrate prone to aggregation is degraded through macroautophagy the autophagosomes carry the substrate for lysosomal hydrolase degradation. Cellular protein quality control can break down nearly all misfolded and aggregated proteins in the human proteome. However, some native and mutant proteins that are vulnerable to aggregating into β-sheet-enriched oligomers tend to be resilient against all designated proteolytic pathways, implying they may transform into inclusion bodies or extracellular plaques. Neurodegenerative diseases are often explained by the buildup of protease-resistant misfolded and aggregated proteins. Neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), prion diseases, Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Here an overview of the neuronal proteolytic pathways is described with special descriptions in UPS, macroautophagy, and CMA. It examines the function of protein quality control at the digestion of distorted pathogenic polypeptides in neurodegenerative diseases. Also, existent potential therapeutic strategies are explored for the efficient removal of cytotoxic proteins from degenerative neuronal cells.