Changes in the Eye May Presage Brain Function Declines

Located in the eye, the retina is made up of neurons with direct connections to the brain. Studying the retina is an easy and accessible way to examine and track changes in neurons.  Researchers at the Gladstone Institutes and University of California/San Francisco (California, USA) report that a loss of cells in the retina is one of the earliest signs of frontotemporal dementia (FTD) in people with a genetic risk for the disorder—even before any changes appear in their behavior.  Michael Ward and colleagues studied a group of individuals who had a certain genetic mutation that is known to result in FTD. They discovered that before any cognitive signs of dementia were present, these individuals showed a significant thinning of the retina compared with people who did not have the gene mutation. The researchers also discovered new mechanisms by which cell death occurs in FTD. As with most complex neurological disorders, there are several changes in the brain that contribute to the development of FTD. In the inherited form researched in the current study, this includes a deficiency of the protein progranulin, which is tied to the mislocalization of another crucial protein, TDP-43, from the nucleus of the cell out to the cytoplasm. In follow-up studies using a genetic mouse model of FTD, the scientists dentified a depletion of TDP-43 from the cell nuclei before any signs of neurodegeneration occurred, signifying that this loss may be a direct cause of the cell death associated with FTD.  TDP-43 levels were shown to be regulated by a third cellular protein called Ran. By increasing expression of Ran, the researchers were able to elevate TDP-43 levels in the nucleus of progranulin-deficient neurons and prevent their death. The study authors submit that: “Our findings establish retinal neurodegeneration as a new phenotype in progranulin-deficient [frontotemporal dementia], and suggest a pathological loop involving reciprocal loss of Ran and nuclear TDP-43 as an underlying mechanism.”