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Buck researchers identify new 'druggable' target for sporadic Parkinson's disease

June 01, 2016

Research at the Buck Institute shows the same mechanisms that lead to neuronal cell death in mice genetically fated to develop Parkinson's disease (PD) are involved in the much more common sporadic form of the age-related, neurodegenerative disorder that robs people of the ability to move normally. The research, published in the journal Neurobiology of Disease identifies new targets that show promise for drug development for an incurable condition that affects as many as one million Americans.

The study focused on parkin - a protein involved in the degradation and purging of both damaged proteins and mitochondria via a process known as lysosomal autophagy. Mutations of parkin are linked to a rare familial form of PD, whereby the cell loses the ability to recycle its internal garbage. PD is characterized by the accumulation of damaged proteins and mitochondria in the area of the brain where the neurotransmitter dopamine is produced.

In this study scientists, led by Buck faculty Julie Andersen, PhD, showed that oxidative stress, which is one of the main drivers of sporadic PD, affected the parkin protein in the same way that genetic mutations do. "This gives us a significant insight into sporadic PD which accounts for 95 percent of all cases of the disease," said Andersen. "We also determined that the signaling pathway involved in the molecular dysfunction is a good target for drug development."

The pathway involves two master regulatory proteins, PGC-1alpha which affects the synthesis of new mitochondria and TFEB which is involved in breaking down old mitochondria. Both are down-regulated following oxidative stress. When scientists genetically increased the expression of PGC-1alpha in the affected mice, mitochondrial function was restored, preventing the degeneration of dopaminergic neurons affected by PD.

Researchers in the Andersen and Lithgow labs are now screening compounds in human cell culture and in nematode worms that have been genetically engineered to develop PD-like characteristics. The goal is to identify compounds that target the pathway and prevent the neurotoxic damage associated with the disease.
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Citation: Neurobiology of Disease, Detrimental effects of oxidative losses in parkin activity in a model of sporadic Parkinson's disease are attenuated by restoration of PGC1 alpha.

DOI: 10.1016/j.nbd 2016.05.009

Other Buck Institute researchers involved in the study include Almas Siddiqui, Shankar Chinta, Anand Rane and Subramanian Rajagopalan. This work was supported by the National Institutes of Health grant AG025901.

About the Buck Institute for Research on Aging

The Buck Institute is the U.S.'s first independent research organization devoted to Geroscience - focused on the connection between normal aging and chronic disease. Based in Novato, CA, The Buck is dedicated to extending "Healthspan", the healthy years of human life and does so utilizing a unique interdisciplinary approach involving laboratories studying the mechanisms of aging and those focused on specific diseases. Buck scientists strive to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer's and Parkinson's, cancer, cardiovascular disease, macular degeneration, osteoporosis, diabetes and stroke. In their collaborative research, they are supported by the most recent developments in genomics, proteomics, bioinformatics and stem cell technologies. For more information: http://www.thebuck.org

Buck Institute for Research on Aging

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