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| http://dx.doi.org/10.1093/hmg/ddaa181 | DOI Listing |
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NLS-binding deficient Kapβ2 reduces neurotoxicity via selective interaction with C9orf72-ALS/FTD dipeptide repeats.
Commun Biol
January 2025
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Arginine-rich dipeptide repeat proteins (R-DPRs) are highly toxic proteins found in patients with C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). R-DPRs can cause toxicity by disrupting the natural phase behavior of RNA-binding proteins (RBPs). Mitigating this abnormal phase behavior is, therefore, crucial to reduce R-DPR-induced toxicity.
View Article and Find Full Text PDFA robust evaluation of TDP-43, poly GP, cellular pathology and behavior in an AAV-C9ORF72 (GC) mouse model.
Acta Neuropathol Commun
December 2024
Brain Science Institute, Johns Hopkins University School of Medicine, Johns Hopkins University, 855 N. Wolfe St., Rangos 275, Baltimore, MD, 21205, USA.
The GC hexanucleotide repeat expansion in C9ORF72 is the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 GC hexanucleotide repeats.
View Article and Find Full Text PDFThe GC hexanucleotide repeat expansion in the major genetic cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Despite considerable efforts, the development of mouse models of C9-ALS/FTD useful for therapeutic development has proven challenging due to the intricate interplay of genetic and molecular factors underlying this neurodegenerative disorder, in addition to species differences. This study presents a robust investigation of the cellular pathophysiology and behavioral outcomes in a previously described AAV mouse model of C9-ALS expressing 66 GC hexanucleotide repeats.
View Article and Find Full Text PDFNeuroprotective effects of activated fibroblast growth factor receptor 1 via the suppression of p53 accumulation against poly-PR-mediated toxicity.
Biochem Biophys Res Commun
January 2025
Laboratory of Medical Therapeutics and Molecular Therapeutics, Japan. Electronic address:
A GGGGCC hexanucleotide repeat expansion (HRE) within the C9orf72 gene is a major causative factor in amyotrophic lateral sclerosis (ALS). This aberrant HRE results in the generation of five distinct dipeptide repeat proteins (DPRs). Among the DPRs, poly-PR accumulates in the nucleus and exhibits particularly strong toxicity to motor and cortical neurons.
View Article and Find Full Text PDFC9orf72-linked arginine-rich dipeptide repeats aggravate pathological phase separation of G3BP1.
Proc Natl Acad Sci U S A
December 2024
Structural Biology Brussels, Bio-engineering Department, Vrije Universiteit Brussel, Elsene 1050, Belgium.
Article Synopsis
- * R-DPRs bind much stronger to the protein G3BP1 than RNA does, promoting the formation of cellular droplets through a process called liquid-liquid phase separation (LLPS), and these droplets can eventually aggregate harmful proteins linked to ALS.
- * Differences in pathology between two types of R-DPRs, poly-GR and poly-PR, suggest that poly-GR primarily targets G3BP1 in stress granules, rather than NPM1 in nucleoli, indicating
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