Proteostasis as a Target for New Intervention in Neurodegenerative Diseases

Dear Colleagues,

Neurons are particularly challenged by protein quality management due to their specific features. Their unique structural organization and postmitotic nature make them very sensitive to the accumulation of toxic compounds, especially misfolded proteins, during aging. Hence, the maintenance of an efficient proteostatic system is of utmost importance for Central Nervous System health, and any condition that affects the timely degradation of misfolded proteins is often associated with neurodegenerative diseases, also known as protein misfolding diseases. Thus far, a growing amount of studies have developed various drugs able to induce the machineries for protein homeostasis (proteostasis), which appear to produce some beneficial effects on the symptoms of these diseases. A variety of chaperones recognize misfolded proteins and assist their refolding or can facilitate their degradation through the protein quality control (PQC) systems that include the ubiquitin–proteasome systems (UPSs), autophagy mechanisms, and endoplasmic reticulum-associated degradation (ERAD). These different systems are aimed at recognizing and preventing a wide plethora of protein misfolding occurrences. Aggregated proteins resistant to these refolding/degradative processes can still be directly managed by chaperones. Given the crucial role of established dysfunction of PQC systems in neurodegenerative diseases, a large consensus indicates the pharmacological activation of proteostatic processes as a promising target for new therapeutic approaches. However, the existence of conflicting results between encouraging preclinical studies and modest outcomes in clinical trials makes this area of investigation a still challenging route that needs further studies. Considering the different mechanisms of action and specific targets within the PQC systems, further efforts are needed to better understand these issues and to improve the feasibility and efficacy of different activators and potential novel therapeutics for protein misfolding diseases. This Special Issue is therefore intended to explore this area of intervention to identify the most suitable therapeutic targets as well as the most critical regulatory mechanisms toward protein homeostasis.

Prof. Dr. Vincenzo G. Nicoletti
Guest Editor

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proteolysis

ubiquitin-proteasome system

autophagy-lysosome system

chaperon-mediated autophagy

macroautophagy

protein quality control

proteolysis activation

protein misfolding diseases