Strategies for the Inhibition of Protein Aggregation in Human Diseases

Abstract

Protein misfolding and aggregation has been related to several human disorders, generally termed protein aggregation diseases. These diseases include neurodegenerative disorders such as Alzheimer's, Parkinson's, and Huntington's diseases and peripheral disorders such as systemic amyloidosis and type 2 diabetes. The complexity of the aggregation processes and the intertwined events account for the fact that no effective disease-modifying treatments for these disorders are currently available. Nevertheless, in-depth research into the aggregation processes has recently yielded major insights into some key mechanisms of aggregation-mediated cell toxicity, offering new targets for drug development. In addition, recent findings in the field have identified similar features, revealing the possibility of shared mechanisms and hence potential common approaches for intervention. This review aims to give an overview of potential strategies for tackling protein aggregation and its associated toxicity, focusing on protein aggregation in human disease.

Thioflavin-S Staining of Bacterial Inclusion Bodies for the Fast, Simple, and Inexpensive Screening of Amyloid Aggregation Inhibitors

“…This increases intermolecular attractive forces favoring the formation of steric zipper (two self-complementary -sheets that form the spine of an amyloid fibril), rendering them prone to self-associate into increasingly ordered and insoluble oligomeric and polymeric species or fibrils [1][2][3]. Amyloidogenic proteins, despite having distinct amino acid composition, length, and in vivo distribution, eventually lead to similar highly ordered aggregated structures.…”

“…A formation and aggregation are thought to trigger a cascade of deleterious events that eventually result in neuronal dysfunction and death and dementia. Thus, the discovery of inhibitors of A aggregation is an area of very active research [2,6,[13][14][15][16], together with that of other A-directed drug candidates aimed at reducing the levels of A in brain by inhibiting its formation (inhibitors of -and -secretases) or by increasing its clearance (active or passive immunotherapy), in the search for effective medications that can delay the onset of AD and slow or halt its progression [16,17].…”

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

“…The absence of well-defined structures is partially the cause of the current reality in which neither the protein self-assembly process nor the interaction of the target proteins with inhibitors or cells is sufficiently understood [20]. Due to these obstacles, most efforts geared at discovering and testing new protein oligomerization inhibitors/modulators for different amyloid-related diseases have relied on empirical observations [21]. A particularly prominent trend has been the use of nutraceuticals -compounds isolated from natural food sources, for which empirical or epidemiological data suggested therapeutic potential [22].…”

Targeting RNA Binding Proteins Involved in Neurodegeneration

“…These strategies include all the various steps of aggregate formation: from approaches aimed at inhibiting basic protein production levels, inhibiting all the various intermediate steps that lead to fibril or filament formation, or achieving the resolubilization of already formed, mature aggregates. 54 To develop a successful therapeutic strategy against any aggregation process, therefore, it is important to obtain information regarding the composition of the aggregates, the genetic or environmental factors that mediate their formation, and especially their significance with regard to the pathological process. As will be described below, this is not an easy or straightforward process even for well-studied proteins such as TDP-43.…”