Diminished Neuronal ESCRT-0 Function Exacerbates AMPA Receptor Derangement and Accelerates Prion-Induced Neurodegeneration
- Jessica A. Lawrence1,
- Patricia Aguilar-Calvo1,
- Daniel Ojeda-Juárez1,
- Helen Khuu1,
- Katrin Soldau1,
- Donald P. Pizzo1,
- Jin Wang1,
- Adela Malik1,
- Timothy F. Shay2,
- Erin E. Sullivan2,
- Brent Aulston3,
- Seung Min Song1,
- Julia A. Callender1,
- Henry Sanchez4,
- Michael D. Geschwind5,
- Subhojit Roy1,3,
- Robert A. Rissman3,
- JoAnn Trejo6,
- Nobuyuki Tanaka7,8,
- Chengbiao Wu3,
- Xu Chen3,
- Gentry N. Patrick9, and
- Christina J. Sigurdson1,10,11
- 1Department of Pathology, University of California, San Diego, La, Jolla, California, 92093
- 2Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125
- 3Department of Neurosciences, University of California, San Diego, La Jolla, California 92093
- 4Department of Pathology, University of California, San Francisco, San Francisco, California 94143
- 5Department of Neurology, Memory and Aging Center, University of California, San Francisco (UCSF), San Francisco, California 94143
- 6Department of Pharmacology, University of California, San Diego, La Jolla, California 92093
- 7Division of Tumor Immunobiology, Miyagi Cancer Center Research Institute, Natori 981-1293, Japan
- 8Division of Tumor Immunobiology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan
- 9Department of Biology, University of California, San Diego, La Jolla, California 92093
- 10Department of Pathology, Microbiology, and Immunology, University of California, Davis, Davis, California 95616
- 11Department of Medicine, University of California, San Diego, La Jolla, California 92093
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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J.W., A.M., T.F.S., E.E.S., B.A., S.M.S., J.A.C., H.S., and C.W. performed research; M.D.G. and R.A.R. contributed unpublished reagents/analytic tools; J.A.L., D.O.-J., J.T., N.T., X.C., G.N.P., and C.J.S. analyzed data; P.A.-C., D.O.-J., and R.A.R. edited the paper; J.A.L. and C.J.S.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.
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.
SIGNIFICANCE STATEMENT Prion diseases are rapidly progressive neurodegenerative disorders characterized by prion aggregate spread through the central nervous system. Early disease features include ubiquitinated protein accumulation and synapse loss. Here, we investigate how prion aggregates alter ubiquitinated protein clearance pathways (ESCRT) in mouse and human prion-infected brain, discovering a marked reduction in Hrs. Using a prion-infection mouse model with neuronal Hrs (nHrs) depleted, we show that low neuronal Hrs is detrimental and markedly shortens survival time while accelerating synaptic derangements, including ubiquitinated protein accumulation, indicating that Hrs loss exacerbates prion disease progression. Additionally, Hrs depletion increases the surface distribution of prion protein (PrPC), linked to aggregate-induced neurotoxic signaling, suggesting that Hrs loss in prion disease accelerates disease through enhancing PrPC-mediated neurotoxic signaling.
- Received October 2, 2022.
- Revision received March 22, 2023.
- Accepted March 27, 2023.
- Copyright © 2023 the authors
