Blazeman Foundation for ALS Research Research Progress Report 5/1/2017 – 5/30/2018

We found that altering levels of TDP-43 led to a strong defect in branching and growth of neurons from the cortical region of the brain, an area that is important in ALS. [...] We tested the first hypothesis by disrupting transport away from the synapse in flies over- expressing TDP-43, by testing if two different mutations in the motor proteins that carry materials away from the synapse could trap the signals at the synapse and restore function. [...] Gad1 plays an important role in limiting accumulation of the neurotransmitter glutamate in the extracellular space, which in turn plays a role in the organization of post-synaptic neurotransmitter receptor. [...] We will reinstate the activation of CREB pathway in the neurons overexpressing TDP- 43, by mechanisms that bypass the requirement for calcium entry, to test if this can alleviate the defects in growth and branching. [...] We will follow up our observation on defects in synapse formation in patient-derived neurons, by testing the density of synapses in cultured rodent neurons when the levels of TDP-43 expression are altered (overexpression and knock-down).