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Neuron. 2019 Aug 7;103(3):412-422.e4. doi: 10.1016/j.neuron.2019.05.030. Epub 2019 Jun 17.

Neuronally Enriched RUFY3 Is Required for Caspase-Mediated Axon Degeneration.

Author information

1
Department of Biology, Stanford University, Stanford, CA, USA; Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY, USA.
2
Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY, USA.
3
Department of Biology, Stanford University, Stanford, CA, USA.
4
Proteomics Resource Center, The Rockefeller University, New York, NY, USA.
5
Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
6
Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
7
Department of Computer Science, Stanford University School of Engineering, Stanford, CA, USA.
8
Department of Biology, Stanford University, Stanford, CA, USA; Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY, USA. Electronic address: tessier3@stanford.edu.

Abstract

Selective synaptic and axonal degeneration are critical aspects of both brain development and neurodegenerative disease. Inhibition of caspase signaling in neurons is a potential therapeutic strategy for neurodegenerative disease, but no neuron-specific modulators of caspase signaling have been described. Using a mass spectrometry approach, we discovered that RUFY3, a neuronally enriched protein, is essential for caspase-mediated degeneration of TRKA+ sensory axons in vitro and in vivo. Deletion of Rufy3 protects axons from degeneration, even in the presence of activated CASP3 that is competent to cleave endogenous substrates. Dephosphorylation of RUFY3 at residue S34 appears required for axon degeneration, providing a potential mechanism for neurons to locally control caspase-driven degeneration. Neuronally enriched RUFY3 thus provides an entry point for understanding non-apoptotic functions of CASP3 and a potential target to modulate caspase signaling specifically in neurons for neurodegenerative disease.

KEYWORDS:

axon degeneration; caspase signaling; chemical biology; degradomics; mass spectrometry; neurodegeneration

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