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Altering Activity of Brain Development Gene Cdk5 Causes Breakdown in Autophagy, Prompting Hyperactive Innate Immunity Attack That Destroys Dopamine-Releasing Neurons in Fly Brains; Similar Process May Occur in Several Neurodegenerative Diseases

In a study of fruit flies, NIH scientists sugges that the body's immune system may play a critical role in the damage caused by aging brain disorders. The results are based on experiments in which the researchers altered the activity of Cdk5, a gene that preclinical studies have suggested is important for early brain development and may be involved in neurodegenerative diseases, such as Lou Gehrig’s disease (ALS), Alzheimer's, and Parkinson's disease. Previously, they found that altering Cdk5 sped up the genetic aging process, causing the flies to die earlier than normal and have problems with walking or flying late in life and greater signs of neurodegenerative brain damage. In the current study, published in the January 2, 2019 issue of Cell Reports, the researchers suggested that altering Cdk5 resulted in the death of dopamine-releasing neurons, especially in the brains of older flies. Typically, Parkinson's disease damages the same types of cells in humans. Further experiments in flies suggested the neuron loss happened because altering Cdk5 slowed autophagy, a cell's waste disposal system that rids the body of damaged cells in a contained, controlled fashion, which, in turn, triggered the immune system to attack the animal's own neurons. This immune system attack is a much "messier" and more diffuse process than autophagy. Genetically, restoring the waste system or blocking the immune system's responses prevented the reduction in dopamine neurons caused by altering Cdk5. The authors concluded that this chain reaction in which a breakdown in autophagy triggers a widely destructive immune reaction may occur in human brain during several neurodegenerative disorders and that researchers may want to look to these systems for new treatment targets and strategies. The open-access Cell Reports article is titled “Hyperactive Innate Immunity Causes Degeneration of Dopamine Neurons Upon Altering Activity of Cdk5.” The senior author of the article is Edward Giniger, PhD, Senior Scientist, NIH's National Institute of Neurological Disorders and Stroke (NINDS).

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In a study of flies, NIH scientists showed how the immune system may be a culprit in the damage caused by aging brain disorders. (Courtesy of Giniger lab, NIH/NINDS).

[Press release] [Cell Reports article]