NICHD scientists identify mechanism for lysosome transportation within neurons
Problems with lysosome distribution disrupt neuron shape, function in rat model
Uneven distribution of lysosomes, the structures that break down unneeded or worn-out cell parts, can impair the shape and function of neurons in rats, according to a study led by researchers at the National Institutes of Health. Problems with lysosomes are known contributors to neurological diseases, and mutations in lysosome-associated genes can increase a person's risk for schizophrenia. However, by providing a better understanding of the normal function and regulation of lysosomes, the current findings may help researchers improve treatment or prevention strategies for neurological disorders. The study appears in the March 20, 2017, issue of PNAS.
Lysosomes break down the cell's unnecessary components, including viruses and bacteria. While lysosomes were discovered in the 1950s, researchers continue to uncover new roles for these structures, including their involvement in neurological disorders. Scientists now know that lysosomes are important for immunity, cell repair, cell migration, and cancer progression, among other functions.
Within a cell, lysosomes must move around to survey the cell's contents and identify targets for degradation or other actions. They rely on a transit system that includes a network of tracks called microtubules. Some proteins help lysosomes move along microtubules to a cell's periphery, while other proteins help them move toward the center. In complex cells like neurons, which consist of projections (called axons and dendrites) jutting out from the cell body, lysosome transport is not well understood.
Researchers led by Juan Bonifacino, Ph.D., of NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, studied lysosome transportation in neurons using rats. They discovered that lysosomes are distributed evenly in all regions of the neuron. Furthermore, they found that lysosomes can move along microtubules in both directions—from dendrites to axon and from axon to dendrites.
Importantly, they also identified a group of proteins—the BORC complex (made up of 8 smaller proteins), Arl8b, SKIP, and kinesin-1—that are responsible for the transportation of lysosomes into the axon area of neurons. When the researchers eliminated or disrupted these proteins, the concentration of lysosomes in the axon decreased. In turn, this reduced the size and shape of the neuron's growth cone—an area that extends to send signals to other tissues. The lack of lysosomes in the axon also affected cell structures called autophagosomes, which deliver their contents to lysosomes for disposal. Without lysosomes, autophagosomes accumulated and remained stationary, unable to discard their contents.
The findings show that uneven distribution of lysosomes disrupts essential cellular processes in neurons.
"One of the subunits of the BORC complex, called BORCS7 or diaskedin, is a schizophrenia susceptibility gene," said Dr. Bonifacino. "But it is unknown how altered expression of BORCS7 may lead to mental health disorders. It's possible that defective lysosome transport may underlie schizophrenia, but more research is needed to explore this idea."
Farías GG, Guardia CM, De Pace R, Britt DJ, and Bonifacino JS. BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon. PNAS DOI: 10.1073/pnas.1616363114 (2017).
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