Medical Research

Salk Institute for Biological Studies

Martin W. Hetzer, Asako McCloskey, Brandon H. Toyama, Travis Berggren 
La Jolla, CA
December 2015

Most healthy individuals experience declines in cognitive performance as they age, suggesting that neuronal functionality decays over time.  This is not surprising as neurons are particularly long-lived compared to most other cell types.  It is therefore critical to untangle the molecular and cellular factors that maintain a youthful neuronal proteome and counteract age-associated or neurodegenerative phenotypes in long-lived neurons.  However, mechanisms governing the maintenance and aging of the proteome are largely unknown because technological challenges have limited the analysis of protein turnover in adult tissues.  To overcome current limitations, a team of Salk Institute investigators developed pulse-chase labeling of rats in combination with quantitative mass spectrometry and multi-isotope image mass spectrometry.  Using this strategy, they identified long-lived proteins (LLPs) that persist in neurons for years.  Importantly, these LLPs perform key regulatory functions, and both neuronal functional decline and specific loss of LLPs in neurons occur during normal aging.  The team plans to decipher the mechanisms underlying the functional integrity of LLPs over long periods of time in rat brain neurons, and determine whether their eventual decline contributes to pathologies in the brain.  The proposed work could provide new avenues for studying the normal aging process and for developing therapies against age-related disease.

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