دورية أكاديمية
أعرض في EDS

VCP activator reverses nuclear proteostasis defects and enhances TDP-43 aggregate clearance in multisystem proteinopathy models.

التفاصيل البيبلوغرافية
العنوان: VCP activator reverses nuclear proteostasis defects and enhances TDP-43 aggregate clearance in multisystem proteinopathy models.
المؤلفون: Phan JM, Creekmore BC, Nguyen AT, Bershadskaya DD, Darwich NF, Mann CN, Lee EB
المصدر: The Journal of clinical investigation [J Clin Invest] 2024 May 23; Vol. 134 (14). Date of Electronic Publication: 2024 May 23.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE
أسماء مطبوعة: Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
مواضيع طبية MeSH: DNA-Binding Proteins*/metabolism , DNA-Binding Proteins*/genetics , Myositis, Inclusion Body*/metabolism , Myositis, Inclusion Body*/pathology , Myositis, Inclusion Body*/genetics , Myositis, Inclusion Body*/drug therapy , Proteostasis* , Valosin Containing Protein*/metabolism , Valosin Containing Protein*/genetics, Animals ; Humans ; Mice ; Cell Nucleus/metabolism ; Frontotemporal Dementia/pathology ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Frontotemporal Dementia/drug therapy ; Intranuclear Inclusion Bodies/metabolism ; Intranuclear Inclusion Bodies/pathology ; Intranuclear Inclusion Bodies/genetics ; Osteitis Deformans/metabolism ; Osteitis Deformans/genetics ; Osteitis Deformans/pathology ; Osteitis Deformans/drug therapy ; Protein Aggregates/drug effects ; TDP-43 Proteinopathies/metabolism ; TDP-43 Proteinopathies/pathology ; TDP-43 Proteinopathies/genetics ; TDP-43 Proteinopathies/drug therapy
مستخلص: Pathogenic variants in valosin-containing protein (VCP) cause multisystem proteinopathy (MSP), a disease characterized by multiple clinical phenotypes including inclusion body myopathy, Paget's disease of the bone, and frontotemporal dementia (FTD). How such diverse phenotypes are driven by pathogenic VCP variants is not known. We found that these diseases exhibit a common pathologic feature: ubiquitinated intranuclear inclusions affecting myocytes, osteoclasts, and neurons. Moreover, knock-in cell lines harboring MSP variants show a reduction in nuclear VCP. Given that MSP is associated with neuronal intranuclear inclusions comprised of TDP-43 protein, we developed a cellular model whereby proteostatic stress results in the formation of insoluble intranuclear TDP-43 aggregates. Consistent with a loss of nuclear VCP function, cells harboring MSP variants or cells treated with VCP inhibitor exhibited decreased clearance of insoluble intranuclear TDP-43 aggregates. Moreover, we identified 4 compounds that activate VCP primarily by increasing D2 ATPase activity, where pharmacologic VCP activation appears to enhance clearance of insoluble intranuclear TDP-43 aggregate. Our findings suggest that VCP function is important for nuclear protein homeostasis, that impaired nuclear proteostasis may contribute to MSP, and that VCP activation may be a potential therapeutic by virtue of enhancing the clearance of intranuclear protein aggregates.
التعليقات: Update of: bioRxiv. 2023 Mar 15:2023.03.15.532082. doi: 10.1101/2023.03.15.532082. (PMID: 36993559)
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معلومات مُعتمدة: T32 AG000255 United States AG NIA NIH HHS; T32 GM007170 United States GM NIGMS NIH HHS; T32 GM132039 United States GM NIGMS NIH HHS; P01 AG066597 United States AG NIA NIH HHS; RF1 AG065341 United States AG NIA NIH HHS; F30 AG077756 United States AG NIA NIH HHS; P30 AG072979 United States AG NIA NIH HHS
فهرسة مساهمة: Keywords: Genetic diseases; Neurodegeneration; Neuroscience; Pharmacology; Therapeutics
المشرفين على المادة: 0 (DNA-Binding Proteins)
0 (Protein Aggregates)
0 (TARDBP protein, human)
EC 3.6.4.6 (Valosin Containing Protein)
EC 3.6.4.6 (VCP protein, human)
تواريخ الأحداث: Date Created: 20240524 Date Completed: 20240715 Latest Revision: 20240804
رمز التحديث: 20240804
مُعرف محوري في PubMed: PMC11257039
DOI: 10.1172/JCI169039
PMID: 38787785
قاعدة البيانات: MEDLINE
الوصف
تدمد:1558-8238
DOI:10.1172/JCI169039