A new study led by the University of California, Irvine, finds that the persistence of a marker of chronic cellular stress, previously associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), it also takes place in Huntington’s brain. patients with disease (HD).
Chronic cellular stress results in the abnormal accumulation of stress granules (SGs), which are groups of proteins and RNAs that come together in the cell. Prior to this study, published in Journal of Clinical Research, it was not known whether these types of granules were a pathological feature of HD, a progressive and inherited neurodegenerative disorder that usually affects in full life.
In addition to identifying SG as a pathological feature of HD, the researchers made several discoveries, including that of extracellular vesicles floating in cerebrospinal fluid (CSF) and act as a messaging system between brain cells, can alter the behavior of other cells and affect the abnormal accumulation of granules. They also found that TAR DNA-binding protein 43 (TDP43) is poorly localized, which has emerged as a critical feature of multiple neurodegenerative diseases.
“We were initially interested in whether the profile of these messages could serve as a biomarker for HD and we investigated whether the vesicles of HD patients contained messages different from those of unaffected people,” said the first author, Isabella I. Sanchez, Ph.D., of the Thompson Laboratory of the UCI School of Medicine.
The researchers found that the CSF of patients with HD carried messages in the form of small non-coding RNAs (miRNAs) that were predicted to alter the production of proteins that are essential for SG formation. They soon identified a key player in the dynamics of SG, GTPase-activating protein-binding protein 1 (G3BP1), as a predicted target.
“This discovery about miRNAs was very exciting, as we had simultaneously initiated research to characterize SGs in HD brain tissues. SGs can be very difficult to detect in brain tissues, and it happened that we had reduced the right conditions and prepared for begin to characterize SG G3BP1 in HD mouse brains and HD patient, “said Leslie M. Thompson, Ph.D., Donald Bren and professor of the ICU Chancellor in the departments of psychiatry and human behavior and biological chemistry of the UCI Faculty of Medicine, and Neurobiology and Behavior at the UCI Faculty of Biological Sciences.
Although SG formation is a normal physiological process that allows cells to overcome stress conditions, SG pathology in HD may result from an accumulation of SG from G3BP1 that initially exerted a protective function, but which is they develop into hyperstable structures over time.
“We hope that our results will inform future studies aimed at understanding how SG accumulation affects HD progression and whether SG pathology is a viable therapeutic pathway in the fight against HD,” said Robert Spitale , doctor to the professor of the department. of Pharmaceutical Sciences and also lead author of the study.
Isabella I. Sanchez et al, Huntington’s disease mice and human brain tissue show increased G3BP1 granules and poor TDP43 localization, Journal of Clinical Research (2021). DOI: 10.1172 / JCI140723
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