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Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover

Seok Heo, Graham H. Diering, Chan Hyun Na, Raja Sekhar Nirujogi, Julia L. Bachman, Akhilesh Pandey and Richard L. Huganir
PNAS April 2, 2018. 201720956; published ahead of print April 2, 2018. https://doi.org/10.1073/pnas.1720956115
Seok Heo
aSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
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Graham H. Diering
aSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
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Chan Hyun Na
bDepartment of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205;cMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;dDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;eInstitute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
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Raja Sekhar Nirujogi
bDepartment of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205;cMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
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Julia L. Bachman
aSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
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Akhilesh Pandey
bDepartment of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205;cMcKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205;fDepartment of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;gDepartment of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;hManipal Academy of Higher Education, Manipal 576104, Karnataka, India;
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  • ORCID record for Akhilesh Pandey
Richard L. Huganir
aSolomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205;iKavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD 21205
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  • For correspondence: rhuganir@jhmi.edu
  1. Contributed by Richard L. Huganir, February 28, 2018 (sent for review December 4, 2017; reviewed by Stephen J. Moss and Angus C. Nairn)

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Significance

The majority of cellular proteins undergo rapid degradation and synthesis to minimize the toxic effect to cells and tissues and to guarantee normal cellular functions. It has been appreciated that proteins with longer half-lives exist in certain cells and tissues. Here we identify synaptic long-lived proteins by high-resolution mass spectrometry. In general, synaptic proteins exhibit slower turnover than cytosolic proteins, and synaptic protein turnover from mouse brain is enhanced by enriched environment exposure. Moreover, protein half-lives are dynamically regulated during changes in neuronal activity. These findings demonstrate the existence of long-lived proteins in synapses in the brain and support a potential role for them in synaptic plasticity and learning and memory.

Abstract

Memory formation is believed to result from changes in synapse strength and structure. While memories may persist for the lifetime of an organism, the proteins and lipids that make up synapses undergo constant turnover with lifetimes from minutes to days. The molecular basis for memory maintenance may rely on a subset of long-lived proteins (LLPs). While it is known that LLPs exist, whether such proteins are present at synapses is unknown. We performed an unbiased screen using metabolic pulse-chase labeling in vivo in mice and in vitro in cultured neurons combined with quantitative proteomics. We identified synaptic LLPs with half-lives of several months or longer. Proteins in synaptic fractions generally exhibited longer lifetimes than proteins in cytosolic fractions. Protein turnover was sensitive to pharmacological manipulations of activity in neuronal cultures or in mice exposed to an enriched environment. We show that synapses contain LLPs that may underlie stabile long-lasting changes in synaptic structure and function.

  • long-lived proteins
  • protein turnover
  • enriched environment
  • neuronal activity
  • mass spectrometry

Footnotes

  • ↵1S.H., G.H.D., and C.H.N. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. Email: rhuganir{at}jhmi.edu.
  • Author contributions: S.H., G.H.D., A.P., and R.L.H. designed research; S.H., G.H.D., C.H.N., R.S.N., and J.L.B. performed research; S.H., G.H.D., and C.H.N. analyzed data; and S.H., G.H.D., C.H.N., and R.L.H. wrote the paper.

  • Reviewers: S.J.M., Tufts University; and A.C.N., Yale University.

  • The authors declare no conflict of interest.

  • Data deposition: All MS data and search results have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD007156 and project name Identification of Long Lived Synaptic Proteins by Comprehensive Proteomic Analysis of Synaptosome Protein Turnover; the data are directly accessible via https://www.ebi.ac.uk/pride/archive/projects/PXD007156.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1720956115/-/DCSupplemental.

Published under the PNAS license.

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Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover
Seok Heo, Graham H. Diering, Chan Hyun Na, Raja Sekhar Nirujogi, Julia L. Bachman, Akhilesh Pandey, Richard L. Huganir
Proceedings of the National Academy of Sciences Apr 2018, 201720956; DOI: 10.1073/pnas.1720956115

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Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover
Seok Heo, Graham H. Diering, Chan Hyun Na, Raja Sekhar Nirujogi, Julia L. Bachman, Akhilesh Pandey, Richard L. Huganir
Proceedings of the National Academy of Sciences Apr 2018, 201720956; DOI: 10.1073/pnas.1720956115
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