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

Abstract

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.

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

“…Extracellular vesicles could play an important role in neurodegeneration as they have been implicated as one route for the spread of misfolded proteins, for instance in Parkinson's disease, and they also contain other cargo such as miRNAs [44]. In HD, our human tissue data indicate that the expression of the HD mutation affects the homeostasis of extracellular vesicles similar to what has been observed before [45]. These findings certainly merit further investigation, in particular because EVs derived from peripheral tissues and biofluids are an attractive source of (peripheral) biomarkers for clinical trials.…”

Key Modulators of the Stress Granule Response TIA1, TDP-43, and G3BP1 are Altered by Polyglutamine Expanded ATXN7

“…However, western blot and IF analyses instead revealed similar or statistically signi cantly increased expression level of these RBPs, suggesting that the stress caused by mutant ATXN7 triggers the stress granule response pathway. As a matter of fact, increased expression of stress granule nucleating proteins has previously been observed in Huntington's disease patients and models [45,46]. Not only were we able to observe an increased level of G3BP1 in our expanded ATXN7 expressing cells, but we also found that the behaviour of G3BP1 changed.…”

Plasma PolyQ-ATXN3 Levels Associate With Cerebellar Degeneration and Behavioral Abnormalities in a New AAV-Based SCA3 Mouse Model

“…Work in cell culture suggests that TDP-43 is sequestered into both pure polyQ aggregates and polyQ-expanded huntingtin inclusions, indicating a potential interaction between these two aggregation-prone proteins ( Fuentealba et al, 2010 ). Co-localization was not observed in a more recent report on Huntington’s disease, however, arguing for further future analysis of this phenotype ( Sanchez et al, 2021 ). Overall, these findings are intriguing, but the differences between the presentation of TDP-43 inclusions in these different polyQ disorders may indicate that TDP-43 pathology is induced by separate pathways in each case.…”

“…The presence of inclusions containing phosphorylated TAR DNA-binding protein 43 (pTDP-43) is a hallmark of several neurodegenerative diseases. Such TDP-43 proteinopathy has not traditionally been associated with polyQ diseases, but inclusions have in fact been reported in SCA3 ( Tan et al, 2009 ; Seidel et al, 2010 ), SCA2 ( Toyoshima et al, 2011 ; Mori et al, 2014 ) and Huntington’s disease patients ( Schwab et al, 2008 ; St-Amour et al, 2018 ; Sanchez et al, 2021 ). To determine whether our model could recapitulate this observation, we used IHC to evaluate the burden of pTDP-43 inclusions in the brains of our Q84 and Q28 mice.…”