These investigators will develop a cellular imaging technique in fruit fly models of three degenerative brain disorders, including Parkinson’s disease, to visualize whether an impaired ability to eliminate mis-folded brain proteins initiates brain cell degeneration.

In biology, UPS stands for the ubiquitin-proteasome system. Normally, this system eliminates from the brain certain proteins that have either mis-folded or abnormally aggregated together. Increasing evidence suggests that accumulation of mis-folded or aggregated proteins in the brain leads to progressive neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, fronto-temporal dementia, and amyotrophic lateral sclerosis (also known as Lou Gehrig’s disease).  Failure of the UPS system to remove defective proteins, therefore, might be pivotal in the onset of neurodegeneration, or it might only be a nonspecific defect involved in any dying cell.  While scientists have speculated that decreased UPS system functioning may initiate neurodegeneration, they have not had the technological capacity to observe the UPS system in living brains (in vivo) to determine whether this is the case.    

Now, St. Jude researchers will develop cellular imaging techniques to enable them to visualize UPS system components in the investigators’ newly developed fruit fly models of Parkinson’s disease, frontotemporal dementia, amyotrophic lateral sclerosis, and spinobulbar muscular atrophy. Why fruit flies? According to the investigators, the fruit fly is ideal for genetic manipulation and its cellular neurobiology can be readily examined with cellular imaging.  The fruit flies will be bred to emit fluorescent light from brain cells, which can be measured using a confocal microscope. While normal brain cells emit slow steady light levels, degrading cells emit rapidly changing lighting. Through this technique, the researchers will monitor UPS function in the fruit fly models of each of multiple neurodegenerative diseases. If they find that UPS system impairment occurs prior to brain cell degradation, the results will provide the first in vivo evidence implicating UPS system impairment in initiating neurodegeneration.

Significance:  If the study provides initial evidence that neurodegeneration is initiated by UPS system impairment, researchers may be able to identify specific therapeutic targets in the UPS pathway to prevent or delay neurodegenerative diseases such as Parkinson’s, Alzheimer's, frontotermporal dementia, and amyotrophic lateral sclerosis.