Fig. 2

TDP-43 pathology in ALS and FTLD-TDP. Physiological TDP-43 is primarily nuclear with some cytoplasm shuttling and can undergo liquid liquid phase separation (LLPS) to form liquid droplets, membrane-less organelles that provide microenvironments for cellular processes. In disease, TDP-43 mislocalises to the cytoplasm and forms insoluble aggregates, possibly through transition from liquid droplets into less-dynamic gel-like state, then solid state aggregates. This process is toxic to the neurons due to a loss of nuclear TDP-43 and gain of TDP-43 aggregates. The neurotoxicity leads to a loss of neurons including upper and lower motor neurons within the motor cortex and spinal cord for ALS (blue), and von Economo neurons and fork cells in the frontoinsular and anterior cingulate cortices for FTLD-TDP (red). Figure constructed using biorender.com