Prions clog cell traffic in brains with neurodegenerative diseases

WASHINGTON — Clumps of misfolded proteins cause traffic jams in brain cells. Those jams may have deadly consequences in neurodegenerative diseases.

Clusters of prions block passage of crucial cargo along intracellular roadways in brain cells, cell biologist Tai Chaiamarit of the Scripps Research Institute in La Jolla, Calif., reported December 10 at the joint annual meeting of the American Society for Cell Biology and the European Molecular Biology Organization.

Prions, misshaped versions of a normal brain protein, clump together in large aggregates that are hallmarks of degenerative brain diseases, such as mad cow disease in cattle, chronic wasting disease in deer and Creutzfeldt-Jakob disease in people. It’s unclear why those clumpy proteins are so deadly to nerve cells called neurons, but the new study may provide clues about what goes wrong in these diseases.

Axons, the long stringlike projections of nerve cells that carry electrical signals to other nerves, are the sites of prion traffic jams, Chaiamarit and colleagues found. As more prions clump together, they cause swollen bulges that make the axon look like a snake that has just swallowed a big meal.

Through a microscope, Chaiamarit and colleagues saw mitochondria being transported toward the cell’s furthest reaches derailed at the bulges.

Mitochondria, cells’ energy-generating organelles, are carried outbound from the main body of the cell by a motor protein called kinesin-1. The protein motors along molecular rails called microtubules. A different motor protein, dynein, transports mitochondria back toward the cell body along those same rails.  

Prion clumps disrupt outbound traffic, causing kinesin-1 and mitochondria to jump the microtubule tracks in the swollen sections, the researchers discovered. Microtubules may be bent or broken in those spots. Mitochondria movement back toward the cell body wasn’t impaired, perhaps because dynein is better at avoiding obstacles than kinesin-1, Chaiamarit said.

Brain cells are alive when the traffic jams start, but the researchers think the jams contribute to cell death later.