Year 4

We are investigating the molecular mechanisms underlying two major neurological diseases: Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease. In the past year, we took our human embryonic stem cell (hESC)-based neural cell culture model for PD and ALS another step further and built sensitive and quantitative assays that can allow for the screening of drug candidates for ALS and PD. We have also consistently improved our transplanting techniques and are now able to detect functional, electrophysiologically active, hESC-derived neurons in live animals. This experiment was crucial to show that, under our culture conditions, human neurons derived from embryonic stem cells were able to integrate and form meaningful connections with other neurons in a given adult brain environment.

Moreover, we are now performing an in-depth characterization of the specific signaling molecules that communicate the inflammation cues from the glial cells to neurons in the presence of ALS-causing mutations (SOD1G37R) and PD-causing mutations (recombinant alfa-synuclein). In this report we have explored another functional assay to measure glial function and inflammatory response using astrocytes that express ALS-causing mutations. In addition, we report here that adding PD-causing mutagens to mixed cultures of human neurons and astrocytes results in the death of dopaminergic neurons, the type of neurons affected in PD. We are currently testing new compounds that can decrease the neuronal toxicity observed.

Our research may not only lead to the discovery of early diagnostic markers but also enable drug screening for compounds that suppress or prevent these neurotoxic inflammatory processes.