Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear. Here we show cellular prion protein (PrP) is found in UBQLN2 inclusions in both mouse and human neuronal induced pluripotent (IPSC) models of UBQLN2 mutations, evidenced by the presence of aggregated forms of PrP with UBQLN2 inclusions. Turnover studies indicated that the P497H UBQLN2 mutation slows PrP protein degradation and leads to mislocalization of PrP in the cytoplasm. Immunoprecipitation studies indicated UBQLN2 and PrP bind together in a complex. The abnormalities in PrP caused by UBQLN2 mutations may be relevant in disease pathogenesis.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.nbd.2024.106674 | DOI Listing |
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11651290 | PMC |
Publication Analysis
Top Keywords
Similar Publications
Analysis of translatomic changes in the model of ALS reveals that motor neurons express muscle-associated genes in non-disease states.
Front Neurol
November 2024
Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN, United States.
Article Synopsis
- ALS is a serious neurodegenerative disease that leads to progressive motor decline and paralysis, with an increase in identified gene mutations highlighting the need for new models to better understand the disease mechanisms.* -
- Researchers created a mouse model with the P497S mutation, which displayed motor symptoms similar to ALS, and by examining gene expression, they found motor neurons showed reduced survival and denervation of neuromuscular junctions at 12 months.* -
- Interestingly, key muscle-related genes were found to be downregulated in motor neurons of affected mice, suggesting these neurons may play a critical role in supporting muscle maintenance despite commonly being associated with muscle tissue.*
Article Synopsis
- The human genome contains sequences from foreign elements, including retrovirus-like proteins, and the study explores how these proteins influence the behavior of UBQLN2, a factor involved in neurodegenerative diseases.
- Two specific retrovirus-like proteins, RTL8 and PEG10, work together to modulate the function of UBQLN2, enabling it to interact with PEG10 and play a role in stress granules during stress conditions.
- The research highlights how PEG10 affects the assembly and disassembly of stress granules and the presence of virus-like particles within them, revealing a novel connection between cellular protein management and retroviral elements.
ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2 phenotypes in Drosophila melanogaster.
Prog Neurobiol
November 2024
Drosophila Centre for Human Diseases and Drug Discovery (DHD), Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. Electronic address:
Article Synopsis
- * Genetic suppression or inhibition of ERO1A in Drosophila models provided neuroprotection and increased lifespan under ER stress conditions.
- * Using the inhibitor EN460 improved motor functions and NMJ structure in models of UBQLN2-related pathology, highlighting ERO1A's potential as a therapeutic target for ER stress-related neurodegenerative diseases.
Prion protein pathology in Ubiquilin 2 models of ALS.
Neurobiol Dis
October 2024
Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, Baltimore, MD, United States of America; Department of Neurobiology, University of Maryland School of Medicine, Baltimore, MD, United States of America.
Mutations in UBQLN2 cause ALS and frontotemporal dementia (FTD). The pathological signature in UBQLN2 cases is deposition of highly unusual types of inclusions in the brain and spinal cord that stain positive for UBQLN2. However, what role these inclusions play in pathogenesis remains unclear.
View Article and Find Full Text PDFWant 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!