<scp><i>PSMC1</i></scp> variant causes a novel neurological syndrome

Aharoni, Sarit; Proskorovski‐Ohayon, Regina; Krishnan, Ramesh Kumar; Yogev, Yuval; Wormser, Ohad; Hadar, Noam; Bakhrat, Anna; Alshafee, Ismael; Gombosh, Maya; Agam, Nadav; Gradstein, Libe; Shorer, Zamir; Zarivach, Raz; Eskin‐Schwartz, Marina; Birk, Ohad S.

doi:10.1111/cge.14195

Cited by 9 publications

(3 citation statements)

References 56 publications

(99 reference statements)

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“…In humans, variance of Psmc1 gene is associated with an autosomal recessive syndrome of severe developmental delay and intellectual disability, hearing loss, and other problems [56]. Impaired learning and memory observed from Psmc1 KO mice are consistent with this clinical data, indicating that impaired proteasome could be a driver for the development of an AD-like phenotype.…”

Section: Discussionsupporting

confidence: 62%

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Impaired 26S proteasome causes learning and memory deficiency and induces neuroinflammation mediated by NF-κB in mice

Huber,

Callegari,

Paez

et al. 2024

Preprint

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Aging and many neurodegenerative disorders, including Alzheimer disease (AD), show reduced proteasome activity, loss of synapses and increased neuroinflammation in the brain. However, whether proteasome dysfunction causes neuroinflammation remains less understood. Here, we studied the effect of impaired 26S proteasome on neuroinflammation in the Psmc1 knockout (KO) mice deficient of a 19S proteasome subunit selectively in the forebrain region. We initially assessed the proteasome activity in the KO and control mouse brains and performed cognitive behavioral test to the animals. The synaptosomes were isolated from the forebrain and subjected to mass spectrometric analysis of total synaptic proteins. The identified synaptic proteins were then assessed using bioinformatic approaches. To validate identified proteins, Western blot analysis and immunofluorescent staining of specific protein were utilized. To validate NF-kB mediating neuroinflammation, we administered the KO animals at 5 weeks of age with a selective NF-kB inhibitor for three weeks and then, animal behaviors and neuroinflammation were assessed when they reached to eight weeks of age. Our results revealed that impaired 26S proteasome led to AD-like cognitive deficiency and overt neuroinflammation in the synapses of the Psmc1 KO brain at eight weeks of age. Pronounced neuroinflammation also occurred in other regions and glial cells, which was confirmed by increased levels of several key immune response-related proteins, including Stat1, Trem2 and NF-kB, and by activation of astrocytes and microglia in the KO brain. Following treating the KO mice with a selective NF-kB inhibitor, the KO mice exhibited improved behaviors and reduced neuroinflammation compared to the control animals. These data indicate that impaired 26S proteasome causes AD-like cognitive deficiency and induces neuroinflammation mediated largely by NF-kB, which will help develop effective therapeutics and aid to better understand the pathogenesis of AD and many other neurodegenerative disorders where impaired proteasome is consistently coupled with neuroinflammation.

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Section: Discussionsupporting

confidence: 62%

“…In humans, variance of Psmc1 gene is associated with an autosomal recessive syndrome of severe developmental delay and intellectual disability, hearing loss, and other problems [56].…”

Section: Discussionmentioning

confidence: 99%

Impaired 26S proteasome causes learning and memory deficiency and induces neuroinflammation mediated by NF-κB in mice

Huber,

Callegari,

Paez

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Protein degradation through the proteasome pathway is tightly regulated by a variety of proteins to prevent random protein degradation. At the core of the proteasome is the 26S proteasome, a multisubunit proteolytic complex consisting of a central catalytic 20S core particle and a 19S regulatory particle ( Aharoni et al, 2022 ). This regulatory particle binds covalently to a polyubiquitin chain on a protein substrate specifically designed for degradation, thereby specifically controlling the proteolytic function of the proteasome.…”

Section: Discussionmentioning

confidence: 99%

Qualitative lysine crotonylation and 2-hydroxyisobutyrylation analysis in the ovarian tissue proteome of piglets

Yang

et al. 2023

Front. Cell Dev. Biol.

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Ovarian function influences diverse aspects of fertility and reproductive lifespan by regulating oocyte supply and hormone secretion. Lysine crotonylation (Kcr) and lysine 2-hydroxyisobutyryllysine (Khib) are newly identified post-translational modifications and function as regulators of transactivation in mammals. In this study, we investigated protein post-translational Kcr and 2-hydroxyisobutyrylation in the ovarian tissues of piglets. A total of 653 overlapping proteins among differentially modified proteins were identified for both crotonylation and 2-hydroxyisobutyrylation. Gene Ontology enrichment analysis indicated that 653 DMPs were significantly enriched in nucleosome organization, chromatin assembly, DNA packaging, peptide biosynthetic process and peptide metabolic process. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed enrichment in proteasome, ribosome, fatty acid elongation, pyruvate metabolism and pentose phosphate pathway. Fifteen DMPs were identified in the proteasome pathway, of which PSMC6 and PSMB7 were the core proteins. In addition, the significant changes in Kcr and Khib in the complex subunits of the proteasome may be involved in cell cycle processes during oocyte development. Forty-four DMPs with both Kcr and Khib modifications were related to the ribosome pathway. The regulated ribosome pathway may indicate that Kcr and Khib comodified proteins participate in protein synthesis during oocyte development. Western blot and immunofluorescence staining results supported the reliability of the sequencing results. Our results may provide a valuable resource to help illuminate the roles of Kcr and Khib in ovarian development and may serve as new tools to better control diseases.

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Proteasome-Associated Syndromes: Updates on Genetics, Clinical Manifestations, Pathogenesis, and Treatment

Zhang,

Tao,

Deuitch

et al. 2024

J Clin Immunol

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PSMC1 variant causes a novel neurological syndrome

Cited by 9 publications

References 56 publications

Impaired 26S proteasome causes learning and memory deficiency and induces neuroinflammation mediated by NF-κB in mice

Impaired 26S proteasome causes learning and memory deficiency and induces neuroinflammation mediated by NF-κB in mice

Qualitative lysine crotonylation and 2-hydroxyisobutyrylation analysis in the ovarian tissue proteome of piglets

Proteasome-Associated Syndromes: Updates on Genetics, Clinical Manifestations, Pathogenesis, and Treatment

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