Huntington's disease mice and human brain tissue exhibit increased G3BP1 granules and TDP43 mislocalization

• Published in: The Journal of clinical investigation 2021-06, Vol.131 (12), p.1-15
• Main Authors: Sanchez, Isabella I, Nguyen, Thai B, England, Whitney E, Lim, Ryan G, Vu, Anthony Q, Miramontes, Ricardo, Byrne, Lauren M, Markmiller, Sebastian, Lau, Alice L, Orellana, Iliana, Curtis, Maurice A, Faull, Richard Lewis Maxwell, Yeo, Gene W, Fowler, Christie D, Reidling, Jack C, Wild, Edward J, Spitale, Robert C, Thompson, Leslie M
• Format: Article
• Language: English
• Subjects: Biomedical research; Brain; Cerebrospinal fluid; Cortex (frontal); Cytoplasm; Deoxyribonucleic acid; Development and progression; DNA; DNA binding proteins; DNA-binding protein; Extracellular vesicles; Gene expression; Genomes; GTPase-activating protein; Health aspects; Huntingtin; Huntington's chorea; Huntington's disease; Huntingtons disease; Hypoxia; Localization; MicroRNA; MicroRNAs; miRNA; Neurodegenerative diseases; Neuropathology; Organelles; Oxidative stress; Pathology; Patients; Physiological aspects; Prefrontal cortex; Protein folding; Proteins; Transgenic mice
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI140723

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology. We examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of HD patients and show that a subset of their target mRNAs were differentially expressed in the prefrontal cortex of HD patients. Of these targets, SG components were enriched, including the SG nucleating Ras GTPase-activating protein-binding protein 1 (G3BP1). We investigated localization and levels of G3BP1 and found a significant increase in the density of G3BP1-positive granules in the cortex and hippocampus of R6/2 transgenic mice and in the superior frontal cortex of HD patient brains. Intriguingly, we also observed that the SG-associated TAR DNA-Binding Protein-43 (TDP43), a nuclear RNA/DNA binding protein, was mislocalized to the cytoplasm of G3BP1-granule positive HD cortical neurons. These findings suggest that G3BP1 SG dynamics may play a role in the pathophysiology of HD.