Diseases of protein aggregation and the hunt for potential pharmacological agents

Abstract

Protein aggregation is a ubiquitous phenomenon significant to all aspects of science. Notably, the formation of protein aggregates is frequently encountered in biochemical research and biopharmaceutical industry. Formation of protein aggregates is generally regarded to be associated with partially folded intermediate species that are susceptible to self-association due to the exposure of hydrophobic core. Evidence supports the concept that the formation of aggregates in vitro is a generic property of proteins. In human etiology, more than 20 different devastating human diseases have been reported to be associated with protein aggregation. Although protein aggregation diseases have been the center of intense research, much remains to be learned regarding the underlying molecular mechanisms. In this review, the general background information on protein aggregation is first provided. Next, we summarize the properties, characteristics and causes of protein aggregates. Finally, from the perspectives of epidemiology, pathogenesis, existing mechanisms, relevant hypotheses, and current as well as potential therapeutic approaches, two examples of protein aggregation diseases, Alzheimer's disease and cataract, are briefly discussed. Importantly, while a variety of molecules have been suggested, the effective therapeutic drugs for curing the diseases involving protein aggregation have yet to be identified. We believe that a better understanding of the mechanisms of protein aggregation process and an extensive investigation into the drug penetration, efficacy, and side effects will certainly aid in developing the successful pharmacological agents for these diseases.

Substrate Recognition in Nuclear Protein Quality Control Degradation Is Governed by Exposed Hydrophobicity That Correlates with Aggregation and Insolubility

“…The exposed hydrophobicity can lead to protein insolubility and the formation of intracellular aggregates (1). Aggregate formation and the long term cellular persistence of aggregates are thought to be the underlying causes of many devastating human pathologies including Alzheimer, Parkinson, Huntington, and amyotrophic lateral sclerosis (2).…”

“…One central means is the elimination of misfolded proteins via protein quality control (PQC) 2 degradation. Eukaryotic PQC degradation is generally mediated by ubiquitin-protein ligases that ubiquitinate misfolded proteins for subsequent proteasome degradation (3).…”

Cellular maintenance of nuclear protein homeostasis

“…As misfolded proteins accumulate and overwhelm the primary PQC systems, they can progressively oligomerize and aggregate in the cell [151]. It is now well understood that the etiology for dozens of degenerative human diseases is linked to the oligomerization and aggregation of misfolded proteins [2, 151]. These diseases are typically characterized by the age-dependent accumulation of pathogenic misfolded proteins into visible cellular inclusions [2, 151].…”

“…It has been revealed that misfolded protein aggregation underlies the pathology for many devastating human disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis (ALS), and prion disorders like Creutzfeldt-Jakob [2]. Presently, it is not clear how misfolding and aggregation cause cellular toxicity in each pathology.…”

Lipid Biomarkers of Lens Aging

“…Understanding the molecular mechanism for cataract formation could be useful for designing alternative treatment or for designing drugs that may delay the onset of the process. Most investigations concerning the causes of cataracts focus on the changes in lens proteins (crystallins) [7,8] since cataract is a disease of protein aggregation [9]; however, since protein stability is maintained by protein-protein, protein-lipid, and other such interactions, alterations in lipid composition of lens could also be a contributing or predisposing factor for development of cataract.…”