Understanding protein turnover alterations in physiological brain aging

Understanding protein turnover alterations in physiological brain aging ABSTRACT In mammals, physiological aging is associated with multiple molecular changes that lead to loss of cellular homeostasis and progressive tissue deterioration. A primary and conserved feature of cellular aging is reduced proteome integrity. Disruption of protein homeostasis machinery leads to accelerated aging in several animal

models and is implicated in human pathology. In the brain, changes in proteome integrity due to extremely slow cell turnover promote the accumulation of damaged and potentially toxic proteins with devastating effects on brain physiology such as cognitive impairment and synapse loss. Interestingly, age is also the strongest risk

factor for several neurodegenerative diseases, raising the question of how age-related proteostasis alterations could become dangerous for the brain and possibly initiate the development of neurodegeneration. While imbalances in protein homeostasis are thought to be a major cause of aging, changes in protein levels in the

aged brain are extremely small. As a result, it has been difficult to study the molecular mechanisms underlying the age-dependent disruption of proteostasis and loss of proteome integrity. Overall, this suggests that we need new analytical paradigms and the development of novel experimental workflows to study loss of proteome

integrity. Along this research line, by using metabolic labeling and quantitative pulsed-SILAC proteomics our team has recently shown that in the brain, aging primarily alters the turnover of a subset of proteins associated with neurodegenerative diseases. This suggests that specific aspects of the protein production/degradation

machinery or the complex assembly state of these proteins are predominantly affected by aging. In other words, there are parts of the proteome that are more susceptible to age-related changes. To understand in detail these protein turnover changes in physiological brain aging and to obtain a quantitative definition of the proteome

imbalance during aging, our proposal will: (I) study the stoichiometry of the ribosome and proteasome; (II) measure changes in protein complex composition at the whole proteome level; (III) reveal for which protein interaction state turnover is more specifically affected by aging; and (IV) address the effects of age-dependent

brain protein aggregation and the extent to which this extends protein lifetimes. Overall, by integrating this wealth of information, we will greatly advance our understanding of the link between brain aging, proteostasis impairment, and the preferential alteration of protein turnover associated with neurodegeneration. Our basic work

will provide new fundamental insights for the entire field of proteostasis impairment in aging and may ultimately lead to new interventions to counteract the decline of the proteome during aging.