Protein folding is the process in which the microscopic particles of the protein interact with one another to cause the protein to assume its conformational shape. Proteins are heterogenous chains, made of building blocks, known as amino acids. Their functional structure gives them the ability to perform specific biological functions, so the way they coil, fold, aggregate, and interact are essential in determining their purpose. With the use of X-ray crystallography and recent technological advancement, it has become increasingly simple to observe a protein’s configuration. 

Even small disruptions in protein homeostasis, such as a mutational change, post-translational modification, or altered quality control systems can alter protein functional efficiency and can even increase pathogenicity. On occasion, protein can irregularly misfold as a result of stochastic fluctuations, the presence of destabilizing mutations, stress conditions, or unique metabolic challenges, such as those that take place as one ages or develops cancer (Chen et al., 2011).  

Chaperones are a family of proteins found in cells that help promote the folding of newly synthesized proteins, the translocation of proteins across membranes, and the refolding of irregularly conformed proteins. Chaperones also play a key role in targeting misfolded proteins for degradation as well as preventing aggregation. Through recent biological experimentation, it has been discovered that there are two distinctly regulated chaperone networks: the chaperones linked to protein synthesis (CLIPS) and the heat shock proteins (HSPs). The CLIPS network is known to be functionally and physically linked to the translation machinery and assist folding of newly translated proteins (Albanese et al. 2006), while the HSP network is induced by heat shock factors and serves to protect the proteome from excessive stress. The ability of molecular chaperones to appropriately and accurately recognize misfolded proteins is essential in order to properly sustain the proteome. However, the molecular process by which chaperones determine whether to fold, degrade, or sequester a misfolded protein in an inclusion is not so clearly understood (Chen et al. 2008). 

A majority of soluble misfolded proteins are cleared through the ubiquitin-proteasome system (UPS), the key eukaryotic proteolytic pathway. In order to guarantee the stability of the proteome, organisms invest in a quality control system that intertwines molecular chaperones, which, as previously discussed mediates protein misfolding, with the UPS and autophagy, which removes misfolded proteins and aggregates. However, the capacity of the proteostasis network (PN) declines as an individual ages, increasing the chances of developing chronic diseases caused by protein aggregation, including neurodegeneration, type II diabetes, heart disease, and certain forms of cancer (Hartl et al. 2016). The UPS necessitates that these proteins are maintained in a non-aggregated state by chaperones, since disposal by autophagy involves active mechanisms to force such molecules into larger, presumably less toxic, aggregates.

Autophagy is a self-induced process in which the body deals with the breakdown of unnecessary or obstructive cellular components. Autophagy most commonly occurs in stressed/ unfavorable conditions. In response to stress, this process has the capacity to remove aggregated proteins and damaged organelles. This has prompted intense interest in autophagy-related therapies for Huntington’s, Alzheimer’s, Parkinson’s, and other neurological diseases. However, excessive or imbalanced induction of autophagic recycling can actively contribute to neuronal atrophy, neurite degeneration, and cell death. This bulk degradative system can be separated into microautophagy, chaperone-mediated autophagy, and macroautophagy, depending on the method of cargo delivery to the lysosome. The most fascinating characteristic of autophagy is the synthesis of double membrane-bound compartments that sequester cellular proteins to be degraded in lytic compartments. Induction of autophagy leads to the formation of cup-shaped membranes in the cytoplasm called phagophores, which expand and eventually seal to become double membrane-bound structures called autophagosomes. 

The brains of patients with Alzheimer’s disease are usually characterized by amyloid‑β‑containing plaques and neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated forms of the microtubule‑associated protein tau (Ittner and Gotz 2011). Step‑wise cleavage of Amyloid Precursor Protein (APP) results in the formation of the 39 to 42 amino‑acid peptide amyloid‑β. Amyloid‑β is prone to aggregation, giving rise to toxic species, including dimers, oligomers and fibrils. On the other hand, Tau, which is predominantly localized in axons, contains three major domains: an amino‑ terminal projection domain, a carboxy‑terminal domain of microtubule‑binding (MTb) repeats and a short tail sequence.