Discussion

Disease modalities such as Parkinson�s, ALS and Alzheimer�s represent complex neurological disorders where certain neuronal populations decline via only partially understood mechanisms that frequently involve neuro-inflammation.

Aim:
- Identify new and disease-relevant, neuroprotective compounds for ALS.
- Model the non-cell autonomous nature of ALS by integrating stem cell-derived motor neurons, astrocytes and activated microglia

Method:
- Screenable phenotypic assay that uses degeneration of motor neurons as primary readout
Diverse secondary assays for mechanism of action studies

Results:
- Identified a small number of neuroprotective compounds in a screen of 11,000 compounds.
- Hit compounds shown to act through multiple
mechanisms:
- inhibition of microglial activation,
- directed protection of neurons from NO stress
- glia-specific activation of genes controlled by Nrf2 transcription factor