Degenerative Protein Modifications in the Aging of the Brain
Researchers here discuss the connection between a declining flow of oxygen to tissues and the level of modified proteins in tissue, particularly in the brain. Modifications tend to render proteins either harmful or at the very least useless for their intended task. This affects cell function and thus also tissue function. It is an open question as to the degree to which impaired clearance versus a faster pace of creation is the important issue, but there is evidence for both to be an issue when the supply of oxygen diminishes, either abruptly due to blood vessel rupture, or more gradually due to vascular aging (loss of capillary density, heart failure, and so forth).
Proteins are the building blocks of life as they are not only the structural constituents of the living organisms but also a final functional molecule governing most of the biological functions. The proteins undergo alterations by spontaneous non-enzymatic Degenerative Protein Modifications (DPMs) including oxidation, deamidation, carbamylation, carbonylation, glycation, etc. The DPMs change protein charge state, hydrophobicity, and three-dimensional structure that influence functional activities and induce aggregation.
These protein modifications and accumulation of modified proteins are allied to aging and the development of age-associated pathologies like neurodegenerative diseases. DPMs like spontaneous protein deamidation characterized by the modification of glutaminyl and asparaginyl residues were hypothesized as a molecular timer of biological events including protein turn over, development and aging. Protein deamidation progressively disrupts structural integrity of the protein and alter their biological activity. Other DPMs including glycation, advanced glycation end products, oxidation, carbonylation, carbamylation, etc., impart deleterious structural and functional changes in proteins and impair their normal function.
Hypoxia, a condition where oxygen supply to tissue is inadequate, induces free radical generation leading to oxidative protein modifications and tissue damage. Oxygen supply also acts as a modulator of aging processes. The cerebrovascular disorders and hypoxia-ischemia injuries in the brain are projected as a primary cause of protein pathologies that leads to cognitive impairment and dementia. In short, hypoxia-ischemia injury in the brain persuades DPMs that can lead to aging, age-associated diseases and neurodegeneration.