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Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.

Publication ,  Journal Article
Küry, S; Stanton, JE; van Woerden, GM; Bosc-Rosati, A; Hsieh, T-C; Bray, L; Oloudé, M; Rosenfelt, C; Scott-Boyer, MP; Most, V; Wang, T; Deb, W ...
Published in: Nat Commun
November 26, 2025

Neurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions, including learning and locomotion. Pharmacological targeting of integrated stress response kinases reveals a mechanistic link between proteotoxic stress and spontaneous type I interferon activation. These findings expand our understanding of proteasome-dependent quality control in neurodevelopment and suggest potential therapeutic strategies for neurodevelopmental proteasomopathies.

Duke Scholars

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

November 26, 2025

Volume

16

Issue

1

Start / End Page

10545

Location

England

Related Subject Headings

  • Proteasome Endopeptidase Complex
  • Neurons
  • Neurodevelopmental Disorders
  • Mitochondria
  • Male
  • Humans
  • Female
  • Drosophila melanogaster
  • Drosophila Proteins
  • Child
 

Citation

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Küry, S., Stanton, J. E., van Woerden, G. M., Bosc-Rosati, A., Hsieh, T.-C., Bray, L., … Krüger, E. (2025). Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies. Nat Commun, 16(1), 10545. https://doi.org/10.1038/s41467-025-65556-8
Küry, Sébastien, Janelle E. Stanton, Geeske M. van Woerden, Amélie Bosc-Rosati, Tzung-Chien Hsieh, Lise Bray, Marielle Oloudé, et al. “Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.Nat Commun 16, no. 1 (November 26, 2025): 10545. https://doi.org/10.1038/s41467-025-65556-8.
Küry S, Stanton JE, van Woerden GM, Bosc-Rosati A, Hsieh T-C, Bray L, et al. Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies. Nat Commun. 2025 Nov 26;16(1):10545.
Küry, Sébastien, et al. “Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.Nat Commun, vol. 16, no. 1, Nov. 2025, p. 10545. Pubmed, doi:10.1038/s41467-025-65556-8.
Küry S, Stanton JE, van Woerden GM, Bosc-Rosati A, Hsieh T-C, Bray L, Oloudé M, Rosenfelt C, Scott-Boyer MP, Most V, Wang T, Papendorf JJ, de Konink C, Deb W, Vignard V, Studencka-Turski M, Besnard T, Hajdukowicz AM, Thiel FG, Wolfgramm S, Florenceau L, Cuinat S, Marsac S, Verrès Y, Dangoumau A, Poirier L, Wentzensen IM, Tuttle A, Forster C, Striesow J, Golnik R, Ortiz D, Jenkins L, Rosenfeld JA, Ziegler A, Houdayer C, Bonneau D, Torti E, Begtrup A, Monaghan KG, Mullegama SV, Volker-Touw CMLN, van Gassen KLI, Oegema R, de Pagter MS, Steindl K, Rauch A, Ivanovski I, McDonald K, Boothe E, Dauber A, Baker J, Fabie NAV, Bernier RA, Turner TN, Srivastava S, Dies KA, Swanson LC, Costin C, Abdulrazak A, Jobling RK, Pappas J, Rabin R, Niyazov D, Chun-Hui Tsai A, Kovak K, Beck DB, Malicdan MCV, Adams DR, Wolfe L, Ganetzky RD, Muraresku CC, Babikyan D, Sedláček Z, Hančárová M, Timberlake AT, Saif HA, Nestler B, King K, Hajianpour MJ, Costain G, Prendergast D, Li C, Geneviève D, Vitobello A, Sorlin A, Philippe C, Harel T, Toker O, Sabir A, Lim D, Hamilton MJ, Bryson LJ, Cleary E, Weber S, Hoffman TL, Cueto-González AM, Tizzano EF, Gómez-Andrés D, Codina-Solà M, Ververi A, Pavlidou E, Lambropoulos A, Garganis K, Rio M, Levy J, Langas SJ, McRae AM, Lessard MK, D’Agostino MD, De Bie I, Wegler M, Abou Jamra R, Kamphausen SB, Bothe V, Potocki L, Olinger E, Sznajer Y, Wiame E, Thompson ML, Schroeder MC, Gooch C, Smith RA, Pandya A, Busch LM, Völker U, Hammer E, Wende K, Cogné B, Isidor B, Meiler J, Ripoll C, Bigou S, Laumonnier F, Hildebrand PW, Eichler EE, McWalter K, Krawitz PM, Roux-Dalvai F, Elgersma Y, Marcoux J, Bousquet M-P, Droit A, Poschmann J, Grabrucker AM, Bolduc FV, Bézieau S, Ebstein F, Krüger E. Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies. Nat Commun. 2025 Nov 26;16(1):10545.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

November 26, 2025

Volume

16

Issue

1

Start / End Page

10545

Location

England

Related Subject Headings

  • Proteasome Endopeptidase Complex
  • Neurons
  • Neurodevelopmental Disorders
  • Mitochondria
  • Male
  • Humans
  • Female
  • Drosophila melanogaster
  • Drosophila Proteins
  • Child