TDP-43 crosses the divide

A protein implicated in amyotrophic lateral sclerosis (ALS) travels between neurons, Feiler et al. show.

The protein TDP-43 may promote the pathology of ALS, in which deterioration of motor neurons leads to paralysis and death. Clumps of the protein accumulate in the motor neurons of patients, and mutations in its gene cause inherited forms of ALS. In individual patients, the illness starts in one location, such as a hand, and then spreads to adjacent body regions. Some evidence suggests that TDP-43 travels between neurons and thus might carry the disease in a prion-like manner, but researchers haven’t confirmed that the protein makes these journeys.

Researchers have debated whether “infectious” proteins like TDP-43 move between neuronal cell bodies or across synapses. Feiler et al. showed that, in culture, TDP-43 travels from the cell body of one motor neuron to the cell body of another. Cells released the proteins inside microvesicles and exosomes, which other cells took up. Using a microfluidic culture system, the team also found that TDP-43 crosses synapses and that this transmission occurs in both directions.

When a cell absorbed TDP-43, the protein interacted with endogenous TDP-43 and seeded the formation of protein clusters. Lysates from postmortem brains of ALS patients also spurred aggregation. The findings indicate that TDP-43 jumps between neurons and therefore might “transmit” the propensity for protein clustering from one cell to another. This behavior could explain why the disease appears to spread in patients.