Identifying determinants of TDP-43 demixing/aggregation to axonal dysfunction in amyotrophic lateral sclerosis (ALS)

Aberrant accumulation of TDP-43 is a nearly universal hallmark of neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a fatal paralytic motor neuron disease for which there is no cure. One of the earliest events in ALS is the disruption of the connections called neuromuscular junctions (NMJs) between muscles and motor neurons leading to the loss of their long projections, the axons. How pathological TDP-43 or ALS-causing mutations provoke the demise of axons/NMJs is not known. TDP-43, which transports and regulates translation of RNAs along axons, forms physiological structures resembling oil droplets in vinegar. Importantly, disease mutations, stress and/or aging may disrupt such unique biophysical properties and underlie axon/NMJ loss. This project will determine whether and how axon-specific properties of TDP-43 are critical for axon and NMJ homeostasis in health and disease and may provide valuable insight for future therapy development to combat neurodegeneration.

Keywords:motor neuron disease, RNA binding proteins, axons

Disciplines:Neurological and neuromuscular diseases