A study led by researchers at Brigham and Women’s Hospital and Harvard Medical School has shed light on the role fatty acids play in Parkinson’s disease and pointed towards an enzyme as a potential therapeutic target for the disease.
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Researchers studying Parkinson’s have become increasingly interested in brain lipids, since previous studies have indicated that disruption to their balance could be an important contributor to the disease.
Now, Saranna Fanning and colleagues have used various model organisms and human cell lines to investigate this hypothesis and identified an enzyme that could be inhibited to protect against neurotoxicity.
People have been aware for many years of some connection between Parkinson's disease and the brain's lipids. Through this collaborative effort, beginning with yeast models in the Lindquist lab and in the Selkoe and Dettmer labs leveraging rat cortical neurons and human cortical neurons, we've identified a pathway and a therapeutic target that no one has pursued before."
Saranna Fanning, Lead Researcher
Fanning’s work began with studies of lipids and fatty acid changes in yeast that had been engineered to produce a protein called α-synuclein (αS).
This protein forms the abnormal protein clumps, called “Lewy bodies,” that form in the brain cells of people with Parkinson’s.
Fanning identified an increase in components of the neutral lipids pathway, including a fatty acid called oleic acid.
Further studies using the classic roundworm C. elegans model, rodent models and human models, including patient cell lines, also led to the same finding.
It was fascinating to see how excess αS had such consistent effects on the neutral lipid pathway across model organisms. All our models clearly pointed at oleic acid as a mediator of α-synuclein toxicity.”
As reported in the journal Molecular Cell, the researchers also assessed neurotoxicity in the models, searching for potential ways to target fatty acids or their pathways that may provide protection against Parkinson’s.
They found that inhibiting an enzyme called stearoyl-CoA-desaturase (SCD), which is involved in the production of oleic acid and other fatty acids, offered this protection.
Many existing SCD inhibitors are already being investigated in research labs, although they are not yet used in the clinic. More follow-up studies would be needed before such research is begun in humans.
The identification of SCD as an enzyme which contributes to α-synuclein-mediated lipid changes and neurotoxicity presents a unique opportunity for small-molecule therapies to inhibit the enzyme in models of PD and, ultimately, in human diseases.”
Dennis Selkoe, Co-author