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Ebstein, F.* ; Küry, S.* ; Most, V.* ; Rosenfelt, C.* ; Scott-Boyer, M.P.* ; van Woerden, G.M.* ; Besnard, T.* ; Papendorf, J.J.* ; Studencka-Turski, M.* ; Wang, T.* ; Hsieh, T.C.* ; Golnik, R.* ; Baldridge, D.* ; Forster, C.* ; de Konink, C.* ; Teurlings, S.M.W.* ; Vignard, V.* ; van Jaarsveld, R.H.* ; Ades, L.* ; Cogné, B.* ; Mignot, C.* ; Deb, W.* ; Jongmans, M.C.J.* ; Cole, F.S.* ; van den Boogaard, M.H.* ; Wambach, J.A.* ; Wegner, D.J.* ; Yang, S.* ; Hannig, V.* ; Brault, J.A.* ; Zadeh, N.* ; Bennetts, B.* ; Keren, B.* ; Gélineau, A.C.* ; Powis, Z.* ; Towne, M.* ; Bachman, K.* ; Seeley, A.* ; Beck, A.E.* ; Morrison, J.* ; Westman, R.* ; Averill, K.* ; Brunet, T. ; Haasters, J.* ; Carter, M.T.* ; Osmond, M.* ; Wheeler, P.G.* ; Forzano, F.* ; Mohammed, S.* ; Trakadis, Y.* ; Accogli, A.* ; Harrison, R.* ; Guo, Y.* ; Hakonarson, H.* ; Rondeau, S.* ; Baujat, G.* ; Barcia, G.* ; Feichtinger, R.G.* ; Mayr, J.A.* ; Preisel, M.* ; Laumonnier, F.* ; Kallinich, T.* ; Knaus, A.* ; Isidor, B.* ; Krawitz, P.* ; Völker, U.* ; Hammer, E.* ; Droit, A.* ; Eichler, E.E.* ; Elgersma, Y.* ; Hildebrand, P.W.* ; Bolduc, F.* ; Kruger, E.* ; Bézieau, S.*

PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production.

Sci. Transl. Med. 15:eabo3189 (2023)
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A critical step in preserving protein homeostasis is the recognition, binding, unfolding, and translocation of protein substrates by six AAA-ATPase proteasome subunits (ATPase-associated with various cellular activities) termed PSMC1-6, which are required for degradation of proteins by 26S proteasomes. Here, we identified 15 de novo missense variants in the PSMC3 gene encoding the AAA-ATPase proteasome subunit PSMC3/Rpt5 in 23 unrelated heterozygous patients with an autosomal dominant form of neurodevelopmental delay and intellectual disability. Expression of PSMC3 variants in mouse neuronal cultures led to altered dendrite development, and deletion of the PSMC3 fly ortholog Rpt5 impaired reversal learning capabilities in fruit flies. Structural modeling as well as proteomic and transcriptomic analyses of T cells derived from patients with PSMC3 variants implicated the PSMC3 variants in proteasome dysfunction through disruption of substrate translocation, induction of proteotoxic stress, and alterations in proteins controlling developmental and innate immune programs. The proteostatic perturbations in T cells from patients with PSMC3 variants correlated with a dysregulation in type I interferon (IFN) signaling in these T cells, which could be blocked by inhibition of the intracellular stress sensor protein kinase R (PKR). These results suggest that proteotoxic stress activated PKR in patient-derived T cells, resulting in a type I IFN response. The potential relationship among proteosome dysfunction, type I IFN production, and neurodevelopment suggests new directions in our understanding of pathogenesis in some neurodevelopmental disorders.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Autism Spectrum Disorders; Protein-kinase; Expression; Mutations; Immunoproteasomes; Neurodegeneration; Flexibility; Degradation; Disruption; Inhibitors
Language english
Publication Year 2023
HGF-reported in Year 2023
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Journal Science Translational Medicine
Quellenangaben Volume: 15, Issue: 698, Pages: , Article Number: eabo3189 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503292-001
Grants Austrian Science Fund (FWF)

Fundamental Research Funds for the Central Universities
Simons Foundation
U.S. National Institutes of Health (NIH)
E-Rare project GENOMIT (Austrian Science Fund FWF)
German Research Foundation
DOI 10.1126/scitranslmed.abo3189
WOS ID 001011583400004
Scopus ID 85160799341
PubMed ID 37256937
Erfassungsdatum 2023-10-06
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