Science Sub-Journal: Significant Progress! Revealed C9orf72 poly (GR) aggregation induces TDP-43 protein lesions.

September 13, 2020 // Repeated amplification in the --- gene C9orf72 can lead to amyotrophic lateral sclerosis (amyotrophic lateral sclerosis, ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases with common characteristics.
TDP-43 (TAR DNA-binding protein 43) enumeration is a pathological feature of FTD and ALS, including cases caused by repeated amplification of G4C2 in the C9orf72 gene (c9FTD/ALS).
alS/FTD patients in the brain with cytocyte TDP-43 aggregates.
mechanism for mediated TDP-43 aggregate formation is not clear.
In a new study, researchers from research institutions such as the Mayo Clinic in the United States and the Perelman School of Medicine at the University of Pennsylvania confirmed that G4C2 repeat sequences formed by repeated amplification of G4C2 in the C9orf72 gene have been expressed to provide new insights into the link between the C9orf72 mutation and the pathology of TDP-43. Poly (GR) is sufficient to facilitate endo-source TDP-43 aggregation.
study was recently published in the journal Science Translational Medicine under the title "C9orf72 poly (GR) aggregation induces TDP-43 proteinopathy".
images from Science Translational Medicine, 2020, doi:10.1126/scitranslmed.abb3774.
particularly, toxic poly (GR) proteins mediate the storage of full-length TDP-43 in a way that RNA does not depend on, thus inducing the formation of cytocytote TDP-43 envelopes.
addition, poly (GR) caused misalposition of nucleocytoplasmic transport factors and nucleo-porous complex proteins in GFP-(GR) 200 mice.
these misalposition events lead to abnormal accumulation of endogenetic TDP-43 in the cytostyte, where it congreges with poly (GR).
In the end, the researchers confirmed that mice that used antisanthion oligonucleotide treatment to express poly (GR) targeting G4C2 repeat sequences reduced poly (GR) loads, along with a decrease in TDP-43 pathology and neurodegeneration, including decreased plasma nerve filament light, NFL concentrations.
These results help shed light on the mechanisms by which poly (GR) drives TDP-43 protein lesions, confirm that G4C2 targeted drugs can reduce the pathology of TDP-43 in the body, and demonstrate that changes in plasma NFL concentration can help to gain insight into the efficacy of disease modification therapy.
(bioon.com) Resources: Casey N. Cook et al. C9orf72 poly (GR) aggregation induces TDP-43 proteinopathy. Science Translational Medicine, 2020, doi:10.1126/scitranslmed.abb3774.