CaltechAUTHORS
Published May 24, 2023 | Version v3
Journal Article Open

Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced Neurodegeneration

Creators

  • 1. ROR icon University of California, San Diego
  • 2. ROR icon California Institute of Technology
  • 3. ROR icon University of California, San Francisco
  • 4. ROR icon Miyagi Prefectural Hospital Organization
  • 5. ROR icon Tohoku University
  • 6. ROR icon University of California, Davis

Abstract

Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity in vivo, we prion-challenged conditional knockout mice (male and female) having Hrs deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prion-affected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration.

Additional Information

© 2023 the authors. Beginning six months after publication the Work will be made freely available to the public on SfN's website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license. The user may not create, compile, publish, host, enable or otherwise make available a mirror site of The Journal of Neuroscience site. This study was supported by National Institutes of Health Grants NS069566 (to C.J.S.), NS076896 (to C.J.S.), K99AG061251 (to P.A.-C.), NS111978 (to S.R.), R35GM127121 (to J.T.), AG031189 (to M.D.G.), AG062562 (to M.D.G.), AG055619 (to M.D.G.), P30AG06429 (to R.A.R., University of California, San Diego Shiley-Marcos Alzheimer's Disease Research Center), NS047101 (University of California, San Diego Microscopy Core), AG062429 (University of California, San Diego Shiley-Marcos Alzheimer's Disease Research Center), and 1S10OD023527 (Electron Microscopy Facility) and by the Michael J. Homer Family Fund (M.D.G.). J.A.L. was supported by a Ruth L. Kirschstein Institutional National Research Award from the National Institutes of Health (F31NS103588). We thank the National Prion Disease Pathology Surveillance Center (NPDPSC) for prion typing and all patients and their families for participating in research. We thank Dr. Mahsa Pourhamzeh for experimental assistance, Dr. Daniela Boassa for valuable discussion of synapse ultrastructure, Timothy Meerloo and Ying Jones at the University of California, San Diego Electron Microscopy Facility for TEM sample preparation, Jennifer Santini at the University of California, San Diego Light Microscopy Core for technical assistance, Jeffrey Metcalf from the laboratory of Dr. Robert Rissman and the Shiley-Marcos Alzheimer's Disease Research Center at University of California, San Diego for providing human tissues for this study, and the animal care staff at University of California, San Diego for excellent animal care. We also thank Dr. Anna Maria Cuervo for the kind gift of the mCherry-GFP-LC3 plasmid and Drs. Markus Glatzel and Hermann Altmeppen for the kind gift of the sPrPG228 antibody. Author contributions: J.A.L., D.P.P., S.R., X.C., and C.J.S. designed the research; J.A.L., P.A.-C., D.O.-J., H.K., K.S., D.P.P., J.W., A.M., T.F.S., E.E.S., B.A., S.M.S., J.A.C., H.S., and C.W. performed research; M.D.G. and R.A.R. contributed unpublished reagents/analytic tools; J.A.L., D.O.-J., J.T., N.T., X.C., G.N.P., and C.J.S. analyzed data; P.A.-C., D.O.-J., and R.A.R. edited the paper; J.A.L. and C.J.S. wrote the paper. The authors declare no competing financial interests.

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Supplemental Material - inline-supplementary-material-2.docx

Supplemental Material - inline-supplementary-material-3.docx

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Additional details

Identifiers

PMCID
PMC10219035
Eprint ID
122356
DOI
10.1523/jneurosci.1878-22.2023
Resolver ID
CaltechAUTHORS:20230719-853619100.5

Related works

Describes
10.1523/jneurosci.1878-22.2023 (DOI)

Funding

NIH
NS069566
NIH
NS076896
NIH
K99AG061251
NIH
NS111978
NIH
R35GM127121
NIH
AG031189
NIH
AG062562
NIH
AG055619
NIH
P30AG06429
NIH
NS047101
NIH
AG062429
NIH
1S10OD023527
Michael J. Homer Family Fund
NIH Postdoctoral Fellowship
F31NS103588

Dates

Created
2023-07-25
Created from EPrint's datestamp field
Updated
2023-07-25
Created from EPrint's last_modified field