Jeffrey Rosenfeld1, Vishwanath Lingappa2
1Neurology, Loma Linda University School Medicine - NEUROLOGY, 2Prosetta Bioscience
Objective:
To introduce a new mechanism in ALS pathogenesis with relevance as a diagnostic assay .
Background:
TDP-43 is mislocalized to the cytoplasm in ALS as a likely mechanism of disease pathogenesis. Using methods developed for study of virus pathogenesis, the mechanism of catalyzed protein assembly was identified as a relevant target in the pathophysiology of ALS. We have identified small molecules with an ability to modulate protein aggregation, analogous to their action in mechanisms of host-catalyzed viral capsid formation. We have termed these small molecules protein assembly modulators.
Design/Methods:
Energy-dependent drug resin affinity chromatography (eDRAC) revealed signature alterations in composition of a peripheral blood mononuclear cell (PBMC) multi-protein complex in ALS patients compared to healthy individuals.
Blinded ALS patients and healthy individual blood samples were obtained under an IRB-approved protocol. Extracts prepared from PBMCs were applied to drug resin and the bound material analyzed.
Results:
Signature changes in the PBMC drug target in ALS patients compared to healthy individuals include diminished p62/SQSTM1 and appearance of a 17 kDa post-translationally modified form of RanGTPase. The ALS patient vs healthy control correlations involving p62 and Ran 17 kDa fragment were accentuated over time with progression of ALS. With disease progression the amount of PBMC p62 in the target multi-protein complex diminishes. and the amount of RanGTPase 17 kDa fragment, (missing in PBMCs from healthy individuals), increases.
Conclusions:
The eDRAC signatures observed appear to have a sensitivity for ALS approaching 100%, can be detected even before serious disability, and are correlated with disease progression. Specificity calculations are underway and will be presented. Our data suggest that this novel assay of catalyzed protein assembly may provide a tool for early detection of ALS using as an affinity ligand a small molecule efficacious in ALS small animal models.
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