Zmpste24 is an integral membrane metalloproteinase of the endoplasmic reticulum. Biochemical studies of tissues from Zmpste24-deficient mice (Zmpste24(-/-)) have indicated a role for Zmpste24 in the processing of CAAX-type prenylated proteins. Here, we report the pathologic consequences of Zmpste24 deficiency in mice. Zmpste24(-/-) mice gain weight slowly, appear malnourished, and exhibit progressive hair loss. The most striking pathologic phenotype is multiple spontaneous bone fractures-akin to those occurring in mouse models of osteogenesis imperfecta. Cortical and trabecular bone volumes are significantly reduced in Zmpste24(-/-) mice. Zmpste24(-/-) mice also manifested muscle weakness in the lower and upper extremities, resembling mice lacking the farnesylated CAAX protein prelamin A. Prelamin A processing was defective both in fibroblasts lacking Zmpste24 and in fibroblasts lacking the CAAX carboxyl methyltransferase Icmt but was normal in fibroblasts lacking the CAAX endoprotease Rce1. Muscle weakness in Zmpste24(-/-) mice can be reasonably ascribed to defective processing of prelamin A, but the brittle bone phenotype suggests a broader role for Zmpste24 in mammalian biology.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC130584 | PMC |
| http://dx.doi.org/10.1073/pnas.192460799 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The Accumulation of Progerin Underlies the Loss of Aortic Smooth Muscle Cells in Hutchinson-Gilford Progeria Syndrome.
bioRxiv
November 2024
Department of Medicine, University of California, Los Angeles; Los Angeles, CA 90095, USA.
Hutchinson-Gilford progeria syndrome (HGPS) is a progeroid disorder characterized by multiple aging-like phenotypes, including disease in large arteries. HGPS is caused by an internally truncated prelamin A (progerin) that cannot undergo the ZMPSTE24-mediated processing step that converts farnesyl-prelamin A to mature lamin A; consequently, progerin retains a carboxyl-terminal farnesyl lipid anchor. In cultured cells, progerin and full-length farnesyl-prelamin A (produced in cells) form an abnormal nuclear lamin meshwork accompanied by nuclear membrane ruptures and cell death; however, these proteins differ in their capacity to cause arterial disease.
View Article and Find Full Text PDFThe NLRP3 inhibitor Dapansutrile improves the therapeutic action of lonafarnib on progeroid mice.
Aging Cell
September 2024
Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, Seville, Spain.
The role of the inflammasomes in aging and progeroid syndromes remain understudied. Recently, MCC950, a NLRP3 inhibitor, was used in Zmpste24 mice to ameliorate the phenotypes. However, the safety of MCC950 was questioned due to liver toxicity observed in humans.
View Article and Find Full Text PDFmiR-29 is an important driver of aging-related phenotypes.
Commun Biol
August 2024
Neuroscience Center; University of North Carolina, Chapel Hill, NC, USA.
Aging is a consequence of complex molecular changes, but whether a single microRNA (miRNA) can drive aging remains unclear. A miRNA known to be upregulated during both normal and premature aging is miR-29. We find miR-29 to also be among the top miRNAs predicted to drive aging-related gene expression changes.
View Article and Find Full Text PDFTIPE2 gene transfer ameliorates aging-associated osteoarthritis in a progeria mouse model by reducing inflammation and cellular senescence.
Mol Ther
September 2024
Center for Regenerative & Personalized Medicine, Steadman Philippon Research Institute, Vail, CO 81657, USA. Electronic address:
Osteoarthritis (OA) pain is often associated with the expression of tumor necrosis factor alpha (TNF-α), suggesting that TNF-α is one of the main contributing factors that cause inflammation, pain, and OA pathology. Thus, inhibition of TNF-α could potentially improve OA symptoms and slow disease progression. Anti-TNF-α treatments with antibodies, however, require multiple treatments and cannot entirely block TNF-α.
View Article and Find Full Text PDFmtDNA release promotes cGAS-STING activation and accelerated aging of postmitotic muscle cells.
Cell Death Dis
July 2024
School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University & Shandong Academy of Medical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Key Lab for Rare & Uncommon Diseases of Shandong Province, Jinan, Shandong, China.
Article Synopsis
- - The study investigates how the cGAS-STING immune signaling pathway influences cellular senescence in postmitotic muscle cells, particularly in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS).
- - Researchers found that aging myofibers in progeria mice showed signs of senescence, mitochondrial DNA damage, and the release of inflammatory SASP factors, indicating a link between mitochondrial dysfunction and immune response.
- - Inhibiting a protein involved in mtDNA release improved muscle cell health by reducing inflammatory responses, suggesting potential new diagnostic and treatment approaches for progeria and related aging muscle disorders.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!