TY - JOUR

T1 - Pathological and Functional Brain Amyloids: A New Concept Explaining the Differences

AU - Галкин, Алексей Петрович

AU - Митькевич, Владимир Александрович

AU - Макаров, Александр Александрович

AU - Валина, Анна Алексеевна

AU - Сысоев, Евгений Игоревич

PY - 2025/10/28

Y1 - 2025/10/28

N2 - In recent years, amyloid proteins that perform vital functions in the brain have been characterized. The question of why some amyloids are neurotoxic while others are harmless remains open. Here, we provide a brief overview of pathological and functional brain amyloids and present a comparative analysis of their amino acid sequences based on the percentage of hydrophobic and charged residues, as well as their enrichment in glutamine, asparagine, serine, and glycine. We demonstrate that pathological and functional brain amyloid proteins, along with their amyloidogenic fragments, do not differ in amino acid composition, contrary to previous assumptions. The ability of an amyloid to cause toxicity can instead be explained by the concept of "available targets". Evidence from studies of pathological amyloids demonstrate that their toxicity is determined not only by a loss of function but also by aberrant interactions with specific targets, such as PrP C or mitochondrial membranes. Binding to these targets triggers pathological cascades that ultimately lead to cell death. In contrast, such targets are inaccessible to functional amyloids, either because of localized translation and protein sequestration within specialized cellular structures, or because their interactions with physiological partners prevent binding to dangerous targets.

AB - In recent years, amyloid proteins that perform vital functions in the brain have been characterized. The question of why some amyloids are neurotoxic while others are harmless remains open. Here, we provide a brief overview of pathological and functional brain amyloids and present a comparative analysis of their amino acid sequences based on the percentage of hydrophobic and charged residues, as well as their enrichment in glutamine, asparagine, serine, and glycine. We demonstrate that pathological and functional brain amyloid proteins, along with their amyloidogenic fragments, do not differ in amino acid composition, contrary to previous assumptions. The ability of an amyloid to cause toxicity can instead be explained by the concept of "available targets". Evidence from studies of pathological amyloids demonstrate that their toxicity is determined not only by a loss of function but also by aberrant interactions with specific targets, such as PrP C or mitochondrial membranes. Binding to these targets triggers pathological cascades that ultimately lead to cell death. In contrast, such targets are inaccessible to functional amyloids, either because of localized translation and protein sequestration within specialized cellular structures, or because their interactions with physiological partners prevent binding to dangerous targets.

KW - Amino Acid Sequence

KW - Amyloid/metabolism

KW - Amyloidogenic Proteins/metabolism

KW - Animals

KW - Brain/metabolism

KW - Humans

KW - pathological targets

KW - amyloidogenic cores

KW - brain

KW - amyloids’ functional partners

KW - comparative analysis

KW - neurodegenerative diseases

KW - neurotoxicity

KW - cellular localization

KW - protein misfolding

KW - functional vs. pathological amyloids

UR - https://www.mendeley.com/catalogue/16d5cae4-6661-33ae-b22a-2af2dcb3fb80/

U2 - 10.3390/ijms262110459

DO - 10.3390/ijms262110459

M3 - Review article

C2 - 41226495

VL - 26

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1422-0067

IS - 21

M1 - 10459

ER -