Abstract
Human neurodegenerative diseases arise from a wide array of genetic and environmental factors. Despite the diversity in etiology, many of these diseases are considered "conformational" in nature, characterized by the accumulation of pathological, misfolded proteins. These misfolded proteins can induce cellular stress by overloading the proteolytic machinery, ultimately resulting in the accumulation and deposition of aggregated protein species that are cytotoxic. Misfolded proteins may also form aberrant, non-physiological protein-protein interactions leading to the sequestration of other normal proteins essential for cellular functions. The progression of such disease may therefore be viewed as a failure of normal protein homeostasis, a process that involves a network of molecules regulating the synthesis, folding, translocation and clearance of proteins. Molecular chaperones are highly conserved proteins involved in the folding of nascent proteins, and the repair of proteins that have lost their typical conformations. These functions have therefore made molecular chaperones an active area of investigation within the field of conformational diseases. This review will discuss the role of molecular chaperones in neurodegenerative diseases, highlighting their functional classification, regulation, and therapeutic potential for such diseases.
Highlights
A significant percentage of the aging population suffers from neurodegenerative conditions, which are among the most intractable of diseases
Chaperones establishes a stringent mechanism of protein quality control (QC) by funneling proteins incapable of appropriately folding through a highly regulated endoplasmic reticulum (ER)-associated degradation pathway (ERAD) [28,29]; as proteins progressing along the secretory pathway lack access to folding support, it is essential that every protein assume its native conformation prior to embarking from the ER [24,30]
Analysis of the open reading frames (ORFs) that contain mutations has revealed alterations in genes encoded for molecular chaperones that may be responsible for some complex human diseases
Summary
A significant percentage of the aging population suffers from neurodegenerative conditions, which are among the most intractable of diseases. Decades of both clinical and basic science research have discovered and characterized dozens of neurodegenerative disorders, triggered by a variety of genetic and environmental factors. Healthy neurons are able to maintain their integrity throughout the lifespan, suggesting the existence of a maintenance mechanism that allows neurons to sustain or even repair damage. Stimulating and augmenting the intrinsic chaperone activity in the nervous system has become a main focus in the design of many neuroprotective strategies. We highlight the mechanisms of chaperone regulation with the focus on augmenting the protective activity of chaperones. We review the pharmacological modulators of molecular chaperones that either have been used or have the potential to be used as therapeutics for neurodegenerative diseases
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