Promising diagnostic, prognostic tools for onset and progression of ALS

Apr 5 2019

Amyotrophic lateral sclerosis is a motor neuron disease with rampant progression and that it is typically fatal within 5 years of prognosis. About 10% of ALS has familial origins that are caused by ~20 genes, whereas the remaining forms of ALS are sporadic. To date there are no effective treatments for ALS. Critical unmet clinical needs in ALS also comprise the lack of predictive tools of the onset and progression of ALS and of druggable mechanisms shared by diverse forms of ALS.

Mounting evidence indicates that the shuttling of selective proteins between the nucleus and cytosolic compartments of motor neurons is impaired across different forms of ALS with cascading consequences. Among these are the apparent and toxic accumulation of proteins that become deleterious to lifelong motor neurons. A team of investigators at Duke University Medical Center led by Dr. Paulo Ferreira and collaborators at Cleveland Clinic, have developed and examined a genetically-modified mouse model with dysregulation of nucleocytoplasmic transport. These mice develop rapidly progressing ALS-like motor traits. Like in ALS patients, the mice develop limb paralysis and succumb to respiratory distress.

Research led by these investigators and published online in Cellular and Molecular Life Sciences by Springer Nature and supported by the National Institutes of Health now show that mice with impairments in nucleocytoplasmic transport in spinal motor and retinal ganglion neurons develop early and functional deficits in visual transmission from the retina to the brain. These visual deficits develop before motor symptoms ensued. Retinal ganglion neurons are specialized cells in the retina, which is a neuronal tissue that lines the back and inside part of the eye. Ganglion neurons through their long projections (axons) transmit to the brain a complex array of visual stimuli that are captured by a network of sensory neurons in the retina. Mice with dysregulation of nucleocytoplasmic transport in retinal ganglion neurons also show the thinning (degeneration) of axons projected to the brain.

The study led by these investigators also found that apart from sharing functional and morphological abnormalities with motor neurons, the retinal ganglion neurons developed unique molecular and cellular signatures. These footprint responses were by and large distinct from those previously discovered in motor neurons. A hallmark feature of the dysregulation of nucleocytoplasmic transport in retinal ganglion neurons was the stimulation of a set of responses by surveillance cells of the immune system of the central nervous system - the microglia - that promote neuroinflammation. Neuroinflammation, when gone awry, is thought to exacerbate neuronal dysfunction and degeneration.

However, the work of the investigators at Duke University and Cleveland Clinic indicate that neuroinflammation and abnormalities in retinal ganglion neurons can be explored as diagnostic and prognostic tools for the onset and progression of motor neuron diseases, such as ALS. Indeed, their findings were inspired by contemporary studies hinting that ALS patients present abnormities in visual transmission to the brain. There is an old proverb that states “The eyes are the window to the soul”. But now the study by the Duke University and Cleveland Clinic investigators reveal that the eyes may also serve as a powerful and predictive tool for neurological diseases that share impairments in nucleocytoplasmic transport. Parenthetically, such impairments are not restricted to ALS, but are also co-opted by other diseases, such as Huntington’s and Alzheimer’s.