Proteomic screen reveals diverse protein transport between connected neurons in the visual system
Lucio M. Schiapparelli,
Pranav Sharma,
Hai-Yan He,
Jianli Li,
Sahil H. Shah,
Daniel B. McClatchy,
Yuanhui Ma,
Han-Hsuan Liu,
Jeffrey L. Goldberg,
John R. Yates, III,
Hollis T. Cline
Affiliations
Lucio M. Schiapparelli
Neuroscience Department and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Pranav Sharma
Neuroscience Department and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Xosomix, 3210 Merryfield Row, San Diego, CA 92121, USA
Hai-Yan He
Neuroscience Department and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Jianli Li
Neuroscience Department and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Sahil H. Shah
Neuroscience Department and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Neuroscience Graduate Program and Medical Scientist Training Program, University of California, San Diego, La Jolla, CA 92093, USA; Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, CA 94303, USA
Daniel B. McClatchy
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Yuanhui Ma
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Han-Hsuan Liu
Neuroscience Department and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA
Jeffrey L. Goldberg
Byers Eye Institute and Spencer Center for Vision Research, Stanford University, Palo Alto, CA 94303, USA
John R. Yates, III
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
Hollis T. Cline
Neuroscience Department and Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Corresponding author
Summary: Intercellular transfer of toxic proteins between neurons is thought to contribute to neurodegenerative disease, but whether direct interneuronal protein transfer occurs in the healthy brain is not clear. To assess the prevalence and identity of transferred proteins and the cellular specificity of transfer, we biotinylated retinal ganglion cell proteins in vivo and examined biotinylated proteins transported through the rodent visual circuit using microscopy, biochemistry, and mass spectrometry. Electron microscopy demonstrated preferential transfer of biotinylated proteins from retinogeniculate inputs to excitatory lateral geniculate nucleus (LGN) neurons compared with GABAergic neurons. An unbiased mass spectrometry-based screen identified ∼200 transneuronally transported proteins (TNTPs) isolated from the visual cortex. The majority of TNTPs are present in neuronal exosomes, and virally expressed TNTPs, including tau and β-synuclein, were detected in isolated exosomes and postsynaptic neurons. Our data demonstrate transfer of diverse endogenous proteins between neurons in the healthy intact brain and suggest that TNTP transport may be mediated by exosomes.
