Compared with the nucleus of a normal fly neuron (left), one from a fly with a common ALS mutation has a damaged nuclear membrane (right) with clusters of nuclear pore protein (red) around its edges. In green, an abnormal cluster of another protein, poly(

Compared with the nucleus of a normal fly neuron (left), one from a fly with a common ALS mutation has a damaged nuclear membrane (right) with clusters of nuclear pore protein (red) around its edges. In green, an abnormal cluster of another protein, poly(

Yubing Lu of the University of Massachusetts Medical School

Plugged pores may cause dementia, other neurological diseases

It is famous for robbing Lou Gehrig of his life and Stephen Hawking of his mobility and voice, but just how amyotrophic lateral sclerosis (ALS) destroys motor neurons in the brain and spinal cord remains a mystery. Now, scientists are converging on an explanation, at least for a fraction of the ALS cases caused by a mutation also associated with a kind of dementia. In cells with the mutation, the new work shows, pores in the membrane separating the nucleus and cytoplasm become clogged, preventing vital molecules from passing through and creating a fatal cellular traffic jam. For now, the work applies only to the mutation dubbed C9orf72—a DNA stutter in which a short nucleotide sequence, GGGGCC, is repeated hundreds to thousands of times in a gene on chromosome 9. Nor do the multiple labs reporting results this week agree on exactly what plugs those nuclear pores and how the cells die. Still, many in the field are calling the work a major breakthrough, and say the findings could point to new therapies, as well as a novel mechanism for neurodegeneration. 

To read the full story, see the 28 August issue of Science.