Exploring the origins of neurodevelopmental proteasomopathies associated with cardiac malformations: are neural crest cells central to certain pathological mechanisms? DOI Creative Commons
Virginie Vignard, Alban‐Elouen Baruteau,

Bérénice Toutain

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 12, 2024

Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These result the dysfunction proteasomes, which are multi-subunit protein complexes essential for maintaining cellular homeostasis. The clinical phenotype these diseases manifests as syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies malformations cardiac outflow tract (OFT). observations suggest that proteasome loss-of-function variants primarily affect specific embryonic cell types serve origins both structures conotruncal portion heart. In this hypothesis article, we propose crest cells (NCCs), highly multipotent population, generates skeleton, mesenchyme well OFT heart, addition to many other derivatives, would exhibit distinctive vulnerability homeostasis perturbations. Herein, introduce diverse compensatory pathways activated response disruption explore their potential implications NCC physiology. Altogether, paper advocates investigating biology within NCCs early cranial offering rationale future exploration laying initial groundwork therapeutic considerations.

Language: Английский

DEGRADATOR: A Gaming Expedition Into Targeted Protein Degradation Therapies DOI
Natalia A. Szulc,

Anna Olchowik,

Patrycja Jaszczak

et al.

Journal of Chemical Education, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

In an era of rapid scientific advancement, the need for engaging educational tools is critical. DEGRADATOR, a 2D computer game, bridges this gap by immersing players in ubiquitin-proteasome system, key pathway cellular protein degradation. Designed aged 12 and above, DEGRADATOR introduces molecular mechanics targeted degradation, including PROTAC drugs. Through 10 levels gameplay combined with quizzes, it represents first-ever resource its kind to make advanced topic accessible amusing. The game was evaluated 97 high school students (age 15–19) during biology classes. Over 75% completed under 30 min, 63% rated highly (4 or 5 out 5) ability enhance their understanding 59% scored more points on final test, indicating substantial knowledge retention. Teachers highlighted game's potential deepening students' comprehension recommended accompanying materials maximize impact. By blending entertainment education, demystifies complex processes, serving as tool popularizing science addressing misconceptions surrounding new therapeutic technologies. Freely available at https://degradator-game.com, complemented teacher resources multimedia materials, ensuring broad applicability. This innovative platform not only supports classroom learning but also fosters curiosity beyond traditional academic settings.

Language: Английский

Citations

0
E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A DOI Creative Commons
Xiaoyan Hao, Zhengwei Hu, Mengjie Li

et al.

The EMBO Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract The carboxyl terminus of Hsc70-interacting protein (CHIP) is pivotal for managing misfolded and aggregated proteins via chaperone networks degradation pathways. In a preclinical rodent model CHIP-related ataxia, we observed that CHIP mutations lead to increased levels phosphodiesterase 9A (PDE9A), whose role in this context remains poorly understood. Here, investigated the molecular mechanisms underlying PDE9A ataxia demonstrated binds PDE9A, facilitating its polyubiquitination autophagic degradation. Conversely, dysfunctional disrupts process, resulting accumulation, cGMP hydrolysis, impaired PKG phosphorylation at serine 19. This cascade further amplifies ultimately disrupting mitophagy triggering neuronal apoptosis. Elevated PKA inhibit degradation, exacerbating dysfunction. Notably, pharmacological inhibition Bay 73-6691 or virus-mediated expression restored balance cGMP/cAMP signalling. These interventions protect against cerebellar neuropathologies, particularly Purkinje neuron Thus, upregulation considerably exacerbates associated with mutations, targeting interaction between an innovative therapeutic strategy ataxia.

Language: Английский

Citations

0
Primary disorders of polyubiquitination: Dual roles in autoinflammation and immunodeficiency DOI
András N. Spaan, Bertrand Boisson, Seth L. Masters

et al.

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(5)

Published: April 15, 2025

The last decades have brought a rapid expansion of the number primary disorders related to polyubiquitination pathways in humans. Most these manifest with two seemingly contradictory clinical phenotypes: autoinflammation, immunodeficiency, or both. We provide an overview molecular pathogenesis disorders, and their role inflammation infection. By focusing on data from human genetic diseases, we explore complexities corresponding phenotypes deficiencies. offer road map for discovery new etiologies. considering triggers that induce inflammation, propose autoinflammation immunodeficiency as continuous phenotypes.

Language: Английский

Citations

0
PSMD11 loss-of-function variants correlate with a neurobehavioral phenotype, obesity, and increased interferon response DOI Creative Commons
Wallid Deb, Cory Rosenfelt, Virginie Vignard

et al.

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 111(7), P. 1352 - 1369

Published: June 12, 2024

Language: Английский

Citations

2
Exploring the origins of neurodevelopmental proteasomopathies associated with cardiac malformations: are neural crest cells central to certain pathological mechanisms? DOI Creative Commons
Virginie Vignard, Alban‐Elouen Baruteau,

Bérénice Toutain

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 12, 2024

Neurodevelopmental proteasomopathies constitute a recently defined class of rare Mendelian disorders, arising from genomic alterations in proteasome-related genes. These result the dysfunction proteasomes, which are multi-subunit protein complexes essential for maintaining cellular homeostasis. The clinical phenotype these diseases manifests as syndromic association involving impaired neural development and multisystem abnormalities, notably craniofacial anomalies malformations cardiac outflow tract (OFT). observations suggest that proteasome loss-of-function variants primarily affect specific embryonic cell types serve origins both structures conotruncal portion heart. In this hypothesis article, we propose crest cells (NCCs), highly multipotent population, generates skeleton, mesenchyme well OFT heart, addition to many other derivatives, would exhibit distinctive vulnerability homeostasis perturbations. Herein, introduce diverse compensatory pathways activated response disruption explore their potential implications NCC physiology. Altogether, paper advocates investigating biology within NCCs early cranial offering rationale future exploration laying initial groundwork therapeutic considerations.

Language: Английский

Citations

0