Unveiling the crucial neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies.
Sébastien KüryJanelle E StantonGeeske M van WoerdenTzung-Chien HsiehCory Scott RosenfeltMarie-Pier Scott-BoyerVictoria MostTianyun WangJonas Johannes PapendorfCharlotte de KoninkWallid DebVirginie VignardMaja Studencka-TurskiThomas BesnardAnna Marta HajdukowiczFranziska ThielSophie MöllerLaëtitia FlorenceauSilvestre CuinatSylvain MarsacIngrid WentzensenAnnabelle TuttleCara ForsterJohanna StriesowRichard GolnikDamara OrtizLaura JenkinsJill Anne RosenfeldAlban ZieglerClara HoudayerDominique BonneauErin TortiAmber BegtrupKristin G MonaghanSureni V MullegamaC M L Nienke Volker-TouwKoen L I van GassenRenske OegemaMirjam de PagterKatharina SteindlAnita RauchIvan IvanovskiKimberly McDonaldEmily BootheAndrew DauberJanice BakerNoelle Andrea V FabieRaphael A BernierTychele N TurnerSiddharth SrivastavaKira A DiesLindsay SwansonCarrie CostinRebekah K JoblingJohn G PappasRachel RabinDmitriy NiyazovAnne Chun-Hui TsaiKaren KovakDavid B BeckMay Christine V MalicdanDavid R AdamsLynne WolfeRebecca D GanetzkyColleen MurareskuDavit BabikyanZdenek SedlacekMiroslava HancarovaAndrew T TimberlakeHind Al SaifBerkley NestlerKayla KingM J HajianpourGregory CostainD'Arcy PrendergastChumei LiDavid GenevieveAntonio VitobelloArthur SorlinChristophe PhilippeTamar HarelOri TokerAtaf Hussain SabirDerek LimMark HamiltonLisa BrysonElaine ClearySacha WeberTrevor L HoffmanAnna Maria Cueto-GonzálezEduardo Fidel TizzanoDavid Gomez AndresMarta Codina SolàAthina VerveriEfterpi PavlidouAlexandros LambropoulosKyriakos GarganisMarlène RioJonathan LevySarah JurgensmeyerAnne M McRaeMathieu Kent LessardMaria Daniela D'AgostinoIsabelle De BieMeret WeglerRami Abou JamraSusanne B KamphausenViktoria BotheLarissa M BuschUwe VölkerElke HammerKristian WendeBenjamin CognéBertrand IsidorJens MeilerAmélie Bosc-RosatiJulien MarcouxMarie-Pierre BousquetJeremie PoschmannFrederic LaumonnierPeter W HildebrandEvan E EichlerKirsty McWalterPeter M KrawitzArnaud DroitYpe ElgersmaAndreas Martin GrabruckerFrancois V BolducStephane BezieauFrédéric EbsteinElke KrügerPublished in: medRxiv : the preprint server for health sciences (2024)
Neurodevelopmental proteasomopathies represent a distinctive category of neurodevelopmental disorders (NDD) characterized by genetic variations within the 26S proteasome, a protein complex governing eukaryotic cellular protein homeostasis. In our comprehensive study, we identified 23 unique variants in PSMC5 , which encodes the AAA-ATPase proteasome subunit PSMC5/Rpt6, causing syndromic NDD in 38 unrelated individuals. Overexpression of PSMC5 variants altered human hippocampal neuron morphology, while PSMC5 knockdown led to impaired reversal learning in flies and loss of excitatory synapses in rat hippocampal neurons. PSMC5 loss-of-function resulted in abnormal protein aggregation, profoundly impacting innate immune signaling, mitophagy rates, and lipid metabolism in affected individuals. Importantly, targeting key components of the integrated stress response, such as PKR and GCN2 kinases, ameliorated immune dysregulations in cells from affected individuals. These findings significantly advance our understanding of the molecular mechanisms underlying neurodevelopmental proteasomopathies, provide links to research in neurodegenerative diseases, and open up potential therapeutic avenues.
Keyphrases
- copy number
- innate immune
- protein protein
- genome wide
- endothelial cells
- cerebral ischemia
- amino acid
- oxidative stress
- binding protein
- cell proliferation
- congenital heart disease
- small molecule
- intellectual disability
- minimally invasive
- spinal cord
- dna methylation
- cancer therapy
- subarachnoid hemorrhage
- blood brain barrier
- autism spectrum disorder
- nlrp inflammasome
- single molecule
- endoplasmic reticulum