Administrative Supplement - Novel Protein Aggregation Inhibitors and Upper Motor Neuron Stabilizers for ALS and other Neurodegenerative Diseases

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ABSTRACT Our collaborative efforts between the Ozdinler and Silverman Laboratories began to reveal the presence of small molecules that can reduce protein aggregation and improve the health of upper motor neurons that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology. We are setting the stage for a cell-based and mechanism-focused drug discovery effort that utilizes upper motor neuron health as a readout. Recently, we also revealed the importance of ion channel homeostasis for upper motor neuron stability and how cortical connectivity is an important aspect of their health and function. Here, we apply to acquire a new equipment, which will allow us to assay and investigate potential improvements in cortical connectivity upon compound administration. Current studies investigate the stability and the cellular integrity of upper motor neurons by studying at cell/neuron structure. However, it is most desirable to reveal whether compound treatments also lead to improved cortical connectivity and function. Novel equipment, which measure field potentials, propagation of connectivity within different regions of the brain at a layer and even at a cellular level resolution has the potential to add tremendous impact to the RO1 grant we currently have. As we continue our investigations on small molecule controls over upper motor neuron health and stability, –via reduced protein aggregation–, we believe that investigation of their neuronal activity at a cellular level, and more broadly within the cortical network, will have an immense impact on our proposal.