Molecular Chaperones in Neurodegeneration: Mechanisms of Regulation in Cellular Proteostasis

Introduction

Cells are the basic unit of life and protein acts as the building block of these basic units thus, within the cell protein homeostasis (proteostasis) is very crucial. Cells have a very developed and sophisticated quality control system called the protein quality control (PQC) system to accomplish proteostasis. This PQC system promotes proteins folding in a proper manner and assists in protein degradation when required. The PQC system involves various biological pathways that are very important for post-mitotic cells, including neurons. Under normal conditions, synthesized polypeptides undergo folding for the formation of native functional conformation. Generation and accumulation of non-functional and misfolded proteins either due to mutations or proteins synthesis faults or inefficient folding of nascent proteins can cause cell toxicity leading to cell death. To prevent these various groups of specific cellular proteins called chaperones were implemented. These chaperones are the primary defense mechanism of a cell against the misfolding of proteins and their subsequent aggregation (Hartl et al., 2011).

Disruption of PQC mechanisms, presence of misfolded proteins along with cellular chaperones and degradation processes are the most common pathological hallmarks of many protein misfolding diseases, including neurodegenerative disorders (Stefani et al., 2003). The quality control machinery from chaperone has a very important role in assembling a protein molecule in three-dimensional conformation. Chaperones are present in an abundant number in the cytoplasm and within the cytoplasmic meshwork, they form complexes with various cytoskeletal components, as well as connected to a large number of other proteins (Soti et al., 2002). Driven by adenosine triphosphate (ATP) cellular chaperones function to prevent misfolding of proteins, engage in the loose folding operation, help fold and refold damaged proteins. Therefore, in protein quality control system chaperones are key components (Tiroli-Cepeda et al., 2011). Proteotoxic stress, age-related decline, molecular overcrowding, and mutations can disrupt the original folding pattern of protein molecules (Sharma et al., 2009). Chaperone complex disruption leads to instability and inaccurate subcellular signaling protein localization (Pratt et al., 2003). Thus, the failure of this essential mechanism of quality control of cellular proteins was reported to have a significant contribution to the pathology of neurodegenerative disorders (Maiti et al., 2014).