Most discussion of protein aggregation is focused on the few proteins that can excessively aggregate to form solid deposits and an associated toxic biochemistry, such as amyloid-β, α-synuclein, tau, and so forth. But many proteins can aggregate to much lesser degrees, particularly when the normal processes of quality assurance and clearance are impaired. Is this broad aggregation of hundreds of specific proteins in cells in aged tissues a sufficiently important contribution to dysfunction to be worth addressing distinctly from the underlying changes in environment and epigenetic regulation of gene expression that cause this issue? That is an interesting question.
Neurodegenerative diseases affect 1 in 12 people globally and remain incurable. Central to their pathogenesis is a loss of neuronal protein maintenance and the accumulation of protein aggregates with aging. We engineered bioorthogonal tools which allowed us to tag the nascent neuronal proteome and study its turnover with aging, its propensity to aggregate, and its interaction with microglia.
We discovered neuronal proteins degraded on average twice as slowly between 4- and 24-month-old mice with individual protein stability differing between brain regions. Further, we describe the aged neuronal 'aggregome' encompassing 574 proteins, nearly 30% of which showed reduced degradation. The aggregome includes well-known proteins linked to disease as well as a trove of proteins previously not associated with neurodegeneration. Unexpectedly, we found 274 neuronal proteins accumulated in microglia with 65% also displaying reduced degradation and/or aggregation with age. Among these proteins, synaptic proteins were highly enriched, suggesting a cascade of events emanating from impaired synaptic protein turnover and aggregation to the disposal of these proteins, possibly by the engulfment of synapses by microglia.
These findings reveal the dramatic loss of neuronal proteome maintenance with aging which could be causal for age-related synapse loss and cognitive decline.
Link: https://doi.org/10.1101/2025.05.20.654652
View the full article at FightAging
