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

Sébastien Küry; Janelle E. Stanton; Geeske M. van Woerden; Amélie Bosc-Rosati; Tzung Chien Hsieh; Lise Bray; Marielle Oloudé; Cory Rosenfelt; Marie Pier Scott-Boyer; Victoria Most; Tianyun Wang; Jonas J. Papendorf; Charlotte de Konink; Wallid Deb; Virginie Vignard; Maja Studencka-Turski; Thomas Besnard; Anna M. Hajdukowicz; Franziska G. Thiel; Sophie Wolfgramm; Laëtitia Florenceau; Silvestre Cuinat; Sylvain Marsac; Yann Verrès; Audrey Dangoumau; Léa Poirier; Ingrid M. Wentzensen; Annabelle Tuttle; Cara Forster; Johanna Striesow; Richard Golnik; Damara Ortiz; Laura Jenkins; Jill A. Rosenfeld; Alban Ziegler; Clara Houdayer; Dominique Bonneau; Erin Torti; Amber Begtrup; Kristin G. Monaghan; Sureni V. Mullegama; Catharina M.L.Nienke Volker-Touw; Koen L.I. van Gassen; Renske Oegema; Mirjam S. de Pagter; Katharina Steindl; Anita Rauch; Ivan Ivanovski; Kimberly McDonald; Emily Boothe; Andrew Dauber; Janice Baker; Noelle Andrea V. Fabie; Raphael A. Bernier; Tychele N. Turner; Siddharth Srivastava; Kira A. Dies; Lindsay C. Swanson; Carrie Costin; Alali Abdulrazak; Rebekah K. Jobling; John Pappas; Rachel Rabin; Dmitriy Niyazov; Anne Chun-Hui Tsai; Karen Kovak; David B. Beck; May Christine V. Malicdan; David R. Adams; Lynne Wolfe; Rebecca D. Ganetzky; Colleen C. Muraresku; Davit Babikyan; Zdeněk Sedláček; Miroslava Hančárová; Andrew T. Timberlake; Hind Al Saif; Berkley Nestler; Kayla King; M. J. Hajianpour; Gregory Costain; D’Arcy Prendergast; Chumei Li; David Geneviève; Antonio Vitobello; Arthur Sorlin; Christophe Philippe; Tamar Harel; Ori Toker; Ataf Sabir; Derek Lim; Mark J. Hamilton; Lisa J. Bryson; Elaine Cleary; Sacha Weber; Trevor L. Hoffman; Anna M. Cueto-González; Eduardo F. Tizzano; David Gómez-Andrés; Marta Codina-Solà; Athina Ververi; Efterpi Pavlidou; Alexandros Lambropoulos; Kyriakos Garganis; Marlène Rio; Jonathan Levy; Sarah J. Langas; Anne M. McRae; Mathieu K. Lessard; Maria Daniela D’Agostino; Isabelle De Bie; Meret Wegler; Rami Abou Jamra; Susanne B. Kamphausen; Viktoria Bothe; Lorraine Potocki; Eric Olinger; Yves Sznajer; Elsa Wiame; Michelle L. Thompson; Molly C. Schroeder; Catherine Gooch; Raphael A. Smith; Arti Pandya; Larissa M. Busch; Uwe Völker; Elke Hammer; Kristian Wende; Benjamin Cogné; Bertrand Isidor; Jens Meiler; Clémentine Ripoll; Stéphanie Bigou; Frédéric Laumonnier; Peter W. Hildebrand; Evan E. Eichler; Kirsty McWalter; Peter M. Krawitz; Florence Roux-Dalvai; Ype Elgersma; Julien Marcoux; Marie Pierre Bousquet; Arnaud Droit; Jeremie Poschmann; Andreas M. Grabrucker; Francois V. Bolduc; Stéphane Bézieau; Frédéric Ebstein; Elke Krüger

doi:10.1038/s41467-025-65556-8

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

Sébastien Küry
, Janelle E. Stanton
, Geeske M. van Woerden
, Amélie Bosc-Rosati
, Tzung Chien Hsieh
, Lise Bray
, Marielle Oloudé
, Cory Rosenfelt
, Marie Pier Scott-Boyer
, Victoria Most
, Tianyun Wang
, Jonas J. Papendorf
, Charlotte de Konink
, Wallid Deb
, Virginie Vignard
, Maja Studencka-Turski
, Thomas Besnard
, Anna M. Hajdukowicz
, Franziska G. Thiel
, Sophie Wolfgramm

Laëtitia Florenceau, Silvestre Cuinat, Sylvain Marsac, Yann Verrès, Audrey Dangoumau, Léa Poirier, Ingrid M. Wentzensen, Annabelle Tuttle, Cara Forster, Johanna Striesow, Richard Golnik, Damara Ortiz, Laura Jenkins, Jill A. Rosenfeld, Alban Ziegler, Clara Houdayer, Dominique Bonneau, Erin Torti, Amber Begtrup, Kristin G. Monaghan, Sureni V. Mullegama, Catharina M.L.Nienke Volker-Touw, Koen L.I. van Gassen, Renske Oegema, Mirjam S. de Pagter, Katharina Steindl, Anita Rauch, Ivan Ivanovski, Kimberly McDonald, Emily Boothe, Andrew Dauber, Janice Baker, Noelle Andrea V. Fabie, Raphael A. Bernier, Tychele N. Turner, Siddharth Srivastava, Kira A. Dies, Lindsay C. Swanson, Carrie Costin, Alali Abdulrazak, Rebekah K. Jobling, John Pappas, Rachel Rabin, Dmitriy Niyazov, Anne Chun-Hui Tsai, Karen Kovak, David B. Beck, May Christine V. Malicdan, David R. Adams, Lynne Wolfe, Rebecca D. Ganetzky, Colleen C. Muraresku, Davit Babikyan, Zdeněk Sedláček, Miroslava Hančárová, Andrew T. Timberlake, Hind Al Saif, Berkley Nestler, Kayla King, M. J. Hajianpour, Gregory Costain, D’Arcy Prendergast, Chumei Li, David Geneviève, Antonio Vitobello, Arthur Sorlin, Christophe Philippe, Tamar Harel, Ori Toker, Ataf Sabir, Derek Lim, Mark J. Hamilton, Lisa J. Bryson, Elaine Cleary, Sacha Weber, Trevor L. Hoffman, Anna M. Cueto-González, Eduardo F. Tizzano, David Gómez-Andrés, Marta Codina-Solà, Athina Ververi, Efterpi Pavlidou, Alexandros Lambropoulos, Kyriakos Garganis, Marlène Rio, Jonathan Levy, Sarah J. Langas, Anne M. McRae, Mathieu K. Lessard, Maria Daniela D’Agostino, Isabelle De Bie, Meret Wegler, Rami Abou Jamra, Susanne B. Kamphausen, Viktoria Bothe, Lorraine Potocki, Eric Olinger, Yves Sznajer, Elsa Wiame, Michelle L. Thompson, Molly C. Schroeder, Catherine Gooch, Raphael A. Smith, Arti Pandya, Larissa M. Busch, Uwe Völker, Elke Hammer, Kristian Wende, Benjamin Cogné, Bertrand Isidor, Jens Meiler, Clémentine Ripoll, Stéphanie Bigou, Frédéric Laumonnier, Peter W. Hildebrand, Evan E. Eichler, Kirsty McWalter, Peter M. Krawitz, Florence Roux-Dalvai, Ype Elgersma, Julien Marcoux, Marie Pierre Bousquet, Arnaud Droit, Jeremie Poschmann, Andreas M. Grabrucker, Francois V. Bolduc, Stéphane Bézieau, Frédéric Ebstein, Elke Krüger

Department of Biological Sciences

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L'institut du Thorax
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Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (Ireland)
Article number	10545
Journal	Nature Communications
Volume	16
Issue number	1
DOIs	https://doi.org/10.1038/s41467-025-65556-8
Publication status	Published - Dec 2025

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10.1038/s41467-025-65556-8

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Küry, S., Stanton, J. E., van Woerden, G. M., Bosc-Rosati, A., Hsieh, T. C., Bray, L., Oloudé, M., Rosenfelt, C., Scott-Boyer, M. P., Most, V., Wang, T., Papendorf, J. J., de Konink, C., Deb, W., Vignard, V., Studencka-Turski, M., Besnard, T., Hajdukowicz, A. M., Thiel, F. G., ... Krüger, E. (2025). Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies. Nature Communications, 16(1), Article 10545. https://doi.org/10.1038/s41467-025-65556-8

@article{02678f47290f46f6a9c225a9cb1e7035,

title = "Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies",

abstract = "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.",

author = "S{\'e}bastien K{\"u}ry and Stanton, \{Janelle E.\} and \{van Woerden\}, \{Geeske M.\} and Am{\'e}lie Bosc-Rosati and Hsieh, \{Tzung Chien\} and Lise Bray and Marielle Oloud{\'e} and Cory Rosenfelt and Scott-Boyer, \{Marie Pier\} and Victoria Most and Tianyun Wang and Papendorf, \{Jonas J.\} and \{de Konink\}, Charlotte and Wallid Deb and Virginie Vignard and Maja Studencka-Turski and Thomas Besnard and Hajdukowicz, \{Anna M.\} and Thiel, \{Franziska G.\} and Sophie Wolfgramm and La{\"e}titia Florenceau and Silvestre Cuinat and Sylvain Marsac and Yann Verr{\`e}s and Audrey Dangoumau and L{\'e}a Poirier and Wentzensen, \{Ingrid M.\} and Annabelle Tuttle and Cara Forster and Johanna Striesow and Richard Golnik and Damara Ortiz and Laura Jenkins and Rosenfeld, \{Jill A.\} and Alban Ziegler and Clara Houdayer and Dominique Bonneau and Erin Torti and Amber Begtrup and Monaghan, \{Kristin G.\} and Mullegama, \{Sureni V.\} and Volker-Touw, \{Catharina M.L.Nienke\} and \{van Gassen\}, \{Koen L.I.\} and Renske Oegema and \{de Pagter\}, \{Mirjam S.\} and Katharina Steindl and Anita Rauch and Ivan Ivanovski and Kimberly McDonald and Emily Boothe and Andrew Dauber and Janice Baker and Fabie, \{Noelle Andrea V.\} and Bernier, \{Raphael A.\} and Turner, \{Tychele N.\} and Siddharth Srivastava and Dies, \{Kira A.\} and Swanson, \{Lindsay C.\} and Carrie Costin and Alali Abdulrazak and Jobling, \{Rebekah K.\} and John Pappas and Rachel Rabin and Dmitriy Niyazov and \{Chun-Hui Tsai\}, Anne and Karen Kovak and Beck, \{David B.\} and Malicdan, \{May Christine V.\} and Adams, \{David R.\} and Lynne Wolfe and Ganetzky, \{Rebecca D.\} and Muraresku, \{Colleen C.\} and Davit Babikyan and Zden{\v e}k Sedl{\'a}{\v c}ek and Miroslava Han{\v c}{\'a}rov{\'a} and Timberlake, \{Andrew T.\} and Saif, \{Hind Al\} and Berkley Nestler and Kayla King and Hajianpour, \{M. J.\} and Gregory Costain and D{\textquoteright}Arcy Prendergast and Chumei Li and David Genevi{\`e}ve and Antonio Vitobello and Arthur Sorlin and Christophe Philippe and Tamar Harel and Ori Toker and Ataf Sabir and Derek Lim and Hamilton, \{Mark J.\} and Bryson, \{Lisa J.\} and Elaine Cleary and Sacha Weber and Hoffman, \{Trevor L.\} and Cueto-Gonz{\'a}lez, \{Anna M.\} and Tizzano, \{Eduardo F.\} and David G{\'o}mez-Andr{\'e}s and Marta Codina-Sol{\`a} and Athina Ververi and Efterpi Pavlidou and Alexandros Lambropoulos and Kyriakos Garganis and Marl{\`e}ne Rio and Jonathan Levy and Langas, \{Sarah J.\} and McRae, \{Anne M.\} and Lessard, \{Mathieu K.\} and D{\textquoteright}Agostino, \{Maria Daniela\} and \{De Bie\}, Isabelle and Meret Wegler and \{Abou Jamra\}, Rami and Kamphausen, \{Susanne B.\} and Viktoria Bothe and Lorraine Potocki and Eric Olinger and Yves Sznajer and Elsa Wiame and Thompson, \{Michelle L.\} and Schroeder, \{Molly C.\} and Catherine Gooch and Smith, \{Raphael A.\} and Arti Pandya and Busch, \{Larissa M.\} and Uwe V{\"o}lker and Elke Hammer and Kristian Wende and Benjamin Cogn{\'e} and Bertrand Isidor and Jens Meiler and Cl{\'e}mentine Ripoll and St{\'e}phanie Bigou and Fr{\'e}d{\'e}ric Laumonnier and Hildebrand, \{Peter W.\} and Eichler, \{Evan E.\} and Kirsty McWalter and Krawitz, \{Peter M.\} and Florence Roux-Dalvai and Ype Elgersma and Julien Marcoux and Bousquet, \{Marie Pierre\} and Arnaud Droit and Jeremie Poschmann and Grabrucker, \{Andreas M.\} and Bolduc, \{Francois V.\} and St{\'e}phane B{\'e}zieau and Fr{\'e}d{\'e}ric Ebstein and Elke Kr{\"u}ger",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41467-025-65556-8",

language = "English (Ireland)",

volume = "16",

journal = "Nature Communications",

issn = "2041-1723",

number = "1",

}

Küry, S, Stanton, JE, van Woerden, GM, Bosc-Rosati, A, Hsieh, TC, 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, DA, 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, MP, Droit, A, Poschmann, J, Grabrucker, AM, Bolduc, FV, Bézieau, S, Ebstein, F & Krüger, E 2025, 'Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies', Nature Communications, vol. 16, no. 1, 10545. https://doi.org/10.1038/s41467-025-65556-8

TY - JOUR

T1 - Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies

AU - Küry, Sébastien

AU - Stanton, Janelle E.

AU - van Woerden, Geeske M.

AU - Bosc-Rosati, Amélie

AU - Hsieh, Tzung Chien

AU - Bray, Lise

AU - Oloudé, Marielle

AU - Rosenfelt, Cory

AU - Scott-Boyer, Marie Pier

AU - Most, Victoria

AU - Wang, Tianyun

AU - Papendorf, Jonas J.

AU - de Konink, Charlotte

AU - Deb, Wallid

AU - Vignard, Virginie

AU - Studencka-Turski, Maja

AU - Besnard, Thomas

AU - Hajdukowicz, Anna M.

AU - Thiel, Franziska G.

AU - Wolfgramm, Sophie

AU - Florenceau, Laëtitia

AU - Cuinat, Silvestre

AU - Marsac, Sylvain

AU - Verrès, Yann

AU - Dangoumau, Audrey

AU - Poirier, Léa

AU - Wentzensen, Ingrid M.

AU - Tuttle, Annabelle

AU - Forster, Cara

AU - Striesow, Johanna

AU - Golnik, Richard

AU - Ortiz, Damara

AU - Jenkins, Laura

AU - Rosenfeld, Jill A.

AU - Ziegler, Alban

AU - Houdayer, Clara

AU - Bonneau, Dominique

AU - Torti, Erin

AU - Begtrup, Amber

AU - Monaghan, Kristin G.

AU - Mullegama, Sureni V.

AU - Volker-Touw, Catharina M.L.Nienke

AU - van Gassen, Koen L.I.

AU - Oegema, Renske

AU - de Pagter, Mirjam S.

AU - Steindl, Katharina

AU - Rauch, Anita

AU - Ivanovski, Ivan

AU - McDonald, Kimberly

AU - Boothe, Emily

AU - Dauber, Andrew

AU - Baker, Janice

AU - Fabie, Noelle Andrea V.

AU - Bernier, Raphael A.

AU - Turner, Tychele N.

AU - Srivastava, Siddharth

AU - Dies, Kira A.

AU - Swanson, Lindsay C.

AU - Costin, Carrie

AU - Abdulrazak, Alali

AU - Jobling, Rebekah K.

AU - Pappas, John

AU - Rabin, Rachel

AU - Niyazov, Dmitriy

AU - Chun-Hui Tsai, Anne

AU - Kovak, Karen

AU - Beck, David B.

AU - Malicdan, May Christine V.

AU - Adams, David R.

AU - Wolfe, Lynne

AU - Ganetzky, Rebecca D.

AU - Muraresku, Colleen C.

AU - Babikyan, Davit

AU - Sedláček, Zdeněk

AU - Hančárová, Miroslava

AU - Timberlake, Andrew T.

AU - Saif, Hind Al

AU - Nestler, Berkley

AU - King, Kayla

AU - Hajianpour, M. J.

AU - Costain, Gregory

AU - Prendergast, D’Arcy

AU - Li, Chumei

AU - Geneviève, David

AU - Vitobello, Antonio

AU - Sorlin, Arthur

AU - Philippe, Christophe

AU - Harel, Tamar

AU - Toker, Ori

AU - Sabir, Ataf

AU - Lim, Derek

AU - Hamilton, Mark J.

AU - Bryson, Lisa J.

AU - Cleary, Elaine

AU - Weber, Sacha

AU - Hoffman, Trevor L.

AU - Cueto-González, Anna M.

AU - Tizzano, Eduardo F.

AU - Gómez-Andrés, David

AU - Codina-Solà, Marta

AU - Ververi, Athina

AU - Pavlidou, Efterpi

AU - Lambropoulos, Alexandros

AU - Garganis, Kyriakos

AU - Rio, Marlène

AU - Levy, Jonathan

AU - Langas, Sarah J.

AU - McRae, Anne M.

AU - Lessard, Mathieu K.

AU - D’Agostino, Maria Daniela

AU - De Bie, Isabelle

AU - Wegler, Meret

AU - Abou Jamra, Rami

AU - Kamphausen, Susanne B.

AU - Bothe, Viktoria

AU - Potocki, Lorraine

AU - Olinger, Eric

AU - Sznajer, Yves

AU - Wiame, Elsa

AU - Thompson, Michelle L.

AU - Schroeder, Molly C.

AU - Gooch, Catherine

AU - Smith, Raphael A.

AU - Pandya, Arti

AU - Busch, Larissa M.

AU - Völker, Uwe

AU - Hammer, Elke

AU - Wende, Kristian

AU - Cogné, Benjamin

AU - Isidor, Bertrand

AU - Meiler, Jens

AU - Ripoll, Clémentine

AU - Bigou, Stéphanie

AU - Laumonnier, Frédéric

AU - Hildebrand, Peter W.

AU - Eichler, Evan E.

AU - McWalter, Kirsty

AU - Krawitz, Peter M.

AU - Roux-Dalvai, Florence

AU - Elgersma, Ype

AU - Marcoux, Julien

AU - Bousquet, Marie Pierre

AU - Droit, Arnaud

AU - Poschmann, Jeremie

AU - Grabrucker, Andreas M.

AU - Bolduc, Francois V.

AU - Bézieau, Stéphane

AU - Ebstein, Frédéric

AU - Krüger, Elke

PY - 2025/12

Y1 - 2025/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105023217892

U2 - 10.1038/s41467-025-65556-8

DO - 10.1038/s41467-025-65556-8

M3 - Article

C2 - 41298377

AN - SCOPUS:105023217892

SN - 2041-1723

VL - 16

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 10545

ER -

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

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