<p>Supplementary Figure S6. Proliferation of colon and breast tumors xenografted in nude mice treated with PU-H71 is restored in a PRKD2-dependent manner.</p>
Repetitive mild traumatic brain injuries (rmTBIs) are serious trauma events responsible for the development of numerous neurodegenerative disorders. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps of the molecular mechanisms responsible for neurodegeneration. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. Using the Closed-Head Impact Model of Engineered Rotational Acceleration, or CHIMERA, we measured neural changes following injury, including brain volume, diffusion tensor imaging, and resting-state functional magnetic resonance imaging coupled with graph theory and functional connectivity analyses. We determined the effect of rmTBI on markers of gliosis and used NanoString-GeoMx to add a digital-spatial protein profiling analysis of neurodegenerative disease-associated proteins in gray and white matter regions. Our analyses revealed aberrant connectivity changes in the thalamus, independent of microstructural damage or neuroinflammation. We also identified distinct changes in the levels of proteins linked to various neurodegenerative processes including total and phospho-tau species and cell proliferation markers. Together, our data show that rmTBI significantly alters brain functional connectivity and causes distinct protein changes in morphologically intact brain areas.
The most common genetic cause of both Amyotrophic Lateral Sclerosis and Frontotemporal Dementia is a microsatellite expansion mutation in the 5′ UTR region of C9orf72. Expansion of the hexanucleotide repeat region of C9orf72 leads to loss of function, RNA foci, and five species of non‐AUG RAN translated dipeptide repeat proteins (GA, GP, GR, PA, & PR). It has been observed that the sense and antisense dipeptide repeat proteins can be translated simultaneously in one cell, however the interplay between the different species has not been heavily investigated. Here we determined that the antisense repeat protein PR is localized to the nucleus, causes cytotoxicity, disrupts nuclear transport, and triggers PERK phosphorylation and p62 puncta accumulation. However, when PR and its sense partner GA were co‐expressed, PR's localization and cytotoxic outputs were significantly altered. In addition, we showed that GA and PR interact through direct binding that leads to structural and morphological changes. We also demonstrate the ability of dipeptide repeat protein species to be released from one cell and taken up by another. Importantly, we demonstrate that co‐expression of distinct DPRs enhances the release of individual peptides. Thus, the combined expression of distinct C9orf72 derived dipeptide repeat species produces cellular outcomes and structural differences that are unique compared to the expression of a single species. Support or Funding Information Not funded This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
