Dzung Do-Ha

Molecular Horizons PhD Exit Seminar - Dzung Do-Ha

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease leading to progressive paralysis. One of the earliest clinical observations in ALS patients is increased excitability (hyperexcitability) of motor neurons in the cortex and spinal cord of ALS patients prior to reduced excitability (hypoexcitability) and deterioration of motor neuron function. The mechanisms that underlie the alterations in electrical signalling of ALS motor neurons throughout disease progression are not yet fully understood. In my PhD, I investigated how intrinsic changes to motor neurons, as well as the failure of glial cells to support motor neuron function, drive excitability changes in ALS. Specifically, my studies focused on how the ALS-causing mutations, CCNFS621G or C9ORF72exp, alter the electrophysiological properties of motor neurons. Using iPSC-derived motor neurons differentiated from ALS patients, whole-cell patch clamping revealed that CCNFS621G and C9ORF72exp motor neurons showed an increase in neuronal firing and ionic currents that govern neuronal excitability, compared to control motor neurons. Together, the data are suggestive of a hyperexcitability phenotype when ALS motor neurons are cultured alone. However, the co-culture of CCNFS621G or C9ORF72exp astrocytes with either ALS or control motor neurons caused the loss of neuronal firing and altered ionic currents. This suggests that ALS astrocytes can mediate the transition from motor neuron hyperexcitability to hypoexcitability. The findings highlight that the cellular crosstalk between motor neurons and astrocytes play a significant role in altering intrinsic neuronal excitability during ALS progression.