Cellular Regulation of Amyloid Formation in Aging and Disease

Abstract

As the population is aging, the incidence of age-related neurodegenerative diseases, such as Alzheimer and Parkinson disease, is growing. The pathology of neurodegenerative diseases is characterized by the presence of protein aggregates of disease specific proteins in the brain of patients. Under certain conditions these disease proteins can undergo structural rearrangements resulting in misfolded proteins that can lead to the formation of aggregates with a fibrillar amyloid-like structure. Cells have different mechanisms to deal with this protein aggregation, where the molecular chaperone machinery constitutes the first line of defense against misfolded proteins. Proteins that cannot be refolded are subjected to degradation and compartmentalization processes. Amyloid formation has traditionally been described as responsible for the proteotoxicity associated with different neurodegenerative disorders. Several mechanisms have been suggested to explain such toxicity, including the sequestration of key proteins and the overload of the protein quality control system. Here, we review different aspects of the involvement of amyloid-forming proteins in disease, mechanisms of toxicity, structural features, and biological functions of amyloids, as well as the cellular mechanisms that modulate and regulate protein aggregation, including the presence of enhancers and suppressors of aggregation, and how aging impacts the functioning of these mechanisms, with special attention to the molecular chaperones.

Keywords: SERF; amyloid; neurodegeneration; protein aggregation; protein quality control.

Figure 1

The aging cell. Important cellular processes are affected during aging. This will result in several cellular phenotypes, including the overload of the protein quality control system, DNA damage, mitochondrial dysfunction, and ER stress, together resulting in vulnerability to cell death.

Figure 2

Toxic mechanism of misfolded proteins. Important cellular processes are affected as a result of misfolded proteins, including overload of the protein quality control (PQC) system, sequestering of functional proteins, disruption of the nuclear core complex and dysfunction of other cellular organelles as mitochondria, ER stress, and trans-Golgi network (the figure focuses on only one intermediate species, other species can be toxic too).

Figure 3

Amyloids in health and disease. Amyloids are present throughout the body in health and diseases, in green examples of functional amyloids described in the section is called “Functional Amyloid”. In red examples of amyloids resulted causing disease, the non-neuropathic systemic amyloidosis AL, ATT, and SAA are located at the point where they are produced, they do however affect multiple organs as the heart and kidney.

Figure 4

Proposed mechanism for amyloid formation. (A) A misfolded protein can be refolded (1), degraded (2), or aggregated (3), the first step in the aggregation pathway involves oligomers, followed by fibril formation around the fibril axis until the initial aggregates. (B) Schematic view of an in vitro assay with the corresponding aggregation stages for each phase (C) formation of liquid droplets.