Bone Marrow Might Restore Motor Skills

Photo: Blood cells

Blood cells "rescued" the mutant
flies; © NCI Visuals Online

The researchers genetically modified flies to exhibit symptoms of ML4, a disease in which nerve cells in the brain and elsewhere die. They discovered that the nerve cell death and progression of the disease is linked to a build-up of toxic waste in cells. Cell death is delayed by introducing normal blood cells into the flies.

The starting point was previous knowledge that the ML4 disease is caused by loss of the human TRPML1 protein, which works in the membranes of the garbage-collector organelles inside of cells. These organelles, lysosomes, break down damaged cellular material. The research team created flies lacking the TRPML gene and then tested the effect of that "knockout" on motor skills.

Healthy, normal flies naturally climb upward quickly after they are tapped down to the bottom of a tube, regardless of their age. But the mutant animals were unable to move up the tubes rapidly. This problem in motor activity worsened in older flies, demonstrating the progressive loss of motor function that characterises ML4.

Without TRPML, cells build up toxic contents and eventually die. The researchers found that the noxious contents then bust out of the dying cells and speed up the demise of neighbouring cells, causing an explosion of cell death that fans the fires of neurodegeneration, intensifying the impaired motor function and retinal degeneration. When the scientists put the TRPML gene back into neurons of the mutant flies, neurodegeneration was prevented and climbing ability restored.

The surprise came when, in a standard control experiment, the researchers hoped to show that it was the presence of normal TRPML in nerve cells, rather than any other cell type, that restored motor function. So they put the normal TRPML gene back into non-nerve cells, in this case blood cells.

Putting TRPML back into blood cells "rescued" the mutant flies from symptoms of the disease, the researchers found: the TRPML-containing blood cells cleared away dying nerve cells before they could release their toxic contents and kill neighbouring cells, thereby preventing rapid neurodegeneration. The researchers are now testing if mice engineered with ML4 recover if bone marrow transplants are used to reconstitute blood cells with normal TRPML.; Source: Johns Hopkins Medicine