NIH Research Festival
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects thousands of patients and their families. 97% of ALS patients display a common pathology where the essential nucleic acid binding protein, TDP-43, is mislocalized outside of neuronal nuclei. Due to its role in RNA splicing, mislocalization of TDP43 results in the aberrant splicing of numerous transcripts, including the inclusion of normally repressed cryptic exons. To understand the early changes associated with nuclear loss of TDP-43, we examined the functional and transcriptomic alterations in a mouse model where TDP-43 is conditionally deleted from motor neurons. These animals develop progressive motor symptoms due to motor neuron loss over the course of 2-3 months of age. However, the exact mechanisms by which loss of TDP-43 results in motor neuron death are not well understood. By compound muscle action potential recordings from the tibialis anterior muscle, we detect a significant reduction in motor neuron function preceding motor neuron loss and muscle denervation. We hypothesize changes in motor neuron gene expression may account for this functional deficit. We performed single nucleus RNA sequencing of lumbar motor neurons to examine changes in gene expression as well as RNA sequencing of the lumbar spinal cord to assess potential mis-splicing of transcripts in this model. We will assess expression of genes involved in establishing motor neuron identity/function, stress response genes, and misregulated pathways to better understand pathological progression associated with loss of TDP-43. Ultimately these findings could provide potential therapeutic approaches for ALS patients.
Scientific Focus Area: Neuroscience
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