New Parkinson's disease drug target revealed through study of fatty acids

The human brain is rich in lipids. Investigators studying Parkinson's disease (PD) have become increasingly interested in lipids since both molecular and genetic studies have pointed to the disruption of the balance of the brain's lipids as a potentially critical contributor to this disease. Beginning in yeast and moving through various model organisms and human cells, a new study led by investigators from Brigham and Women's Hospital and Harvard Medical School has provided insights into the role of fatty acids and suggests that inhibiting a specific enzyme can protect against neurotoxicity. Their findings, which point to a novel therapeutic approach that could be developed to treat PD and some forms of Alzheimer's disease, are published in Molecular Cell.

"People have been aware for many years of some connection between Parkinson's disease and the brain's lipids," said lead author Saranna Fanning, PhD, of the Ann Romney Center for Neurologic Diseases at the Brigham and Harvard Medical School. "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."

Fanning's work began in the lab of the Whitehead Institute's Susan Lindquist, PhD, who passed away in 2016. She performed unbiased lipidomic profiling, measuring lipids and fatty acid changes in yeast that had been engineered to produce α-synuclein, a protein that forms the hallmark Lewy body clumps of PD. An increase was identified in the constituents of the neutral lipids pathway, including a monounsaturated fatty acid known as oleic acid. This finding was then replicated in rodent and human neuronal models, including patient cell lines, by Fanning and colleagues in the labs of co-senior authors Dennis Selkoe, MD, and Ulf Dettmer, PhD, at the Brigham. Additional experiments were carried out in the roundworm C. elegans, another classic model organism.

"It was fascinating to see how excess αS had such consistent effects on the neutral lipid pathway across model organisms, from simple baker's yeast and cultured rodent neurons to cells derived from PD patients that carry extra copies of α-synuclein in their genome. All our models clearly pointed at oleic acid as a mediator of α-synuclein toxicity," said Dettmer.

The team also measured signs of neurotoxicity in their models, looking for ways to target fatty acids or the pathways involved in their generation that would offer protection from PD. The researchers found that suppressing an enzyme known as stearoyl-CoA-desaturase (SCD), which helps generate oleic acid and other monounsaturated fatty acids, was protective, suggesting that SCD may be a promising therapeutic target.

While not currently used in the clinic, multiple inhibitors of SCD exist today and are used in research labs. Additional follow-up studies will be required to determine how well such testing begins 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," said Selkoe.

Saranna Fanning, Aftabul Haque, Thibaut Imberdis, Valeriya Baru, M Inmaculada Barrasa, Silke Nuber, Daniel Termine, Nagendran Ramalingam, Gary P H Ho, Tallie Noble, Jackson Sandoe, Yali Lou, Dirk Landgraf, Yelena Freyzon, Gregory Newby, Frank Soldner, Elizabeth Terry-Kantor, Tae-Eun Kim, Harald F Hofbauer, Michel Becuwe, Rudolf Jaenisch, David Pincus, Clary B Clish, Tobias C Walther, Robert V Farese Jr, Supriya Srinivasan, Michael A Welte, Sepp D Kohlwein, Ulf Dettmer, Susan Lindquist, Dennis Selkoe.
Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment.
Molecular Cell, 4 December 2018. doi: 10.1016/j.molcel.2018.11.028.

Most Popular Now

Novartis rises to second place in 2018 Access to M…

Novartis ranked second in the 2018 Access to Medicine Index (ATMi), up from 3rd place in 2016, in recognition of its long-standing efforts to improve worldwide access to ...

MSD is looking for a digital health solution to em…

MSD Lebanon is looking for an external partner to co-create a digital solution that helps oncologists to stay updated with relevant clinical content about cancer. The sol...

Sanofi builds focus on rare blood disorders and ca…

Some of the most serious unmet patient needs today are in the field of hematology. Rare blood disorders and blood-related cancers continue to be a major focus of research...

Lilly submits New Drug Application to the FDA for …

Eli Lilly and Company (NYSE: LLY) has announced the submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for lasmiditan for the acute...

FDA approves new treatment for patients with acute…

The U.S. Food and Drug Administration today approved Daurismo (glasdegib) tablets to be used in combination with low-dose cytarabine (LDAC), a type of chemotherapy, for t...

Merck and Pfizer provide update on avelumab in pla…

Merck and Pfizer Inc. (NYSE: PFE) today announced that the Phase III JAVELIN Ovarian 200 trial evaluating avelumab* alone or in combination with pegylated liposomal doxor...

New study reveals probiotics do not help children …

Probiotics are a multibillion-dollar industry with marketing claims of being an effective treatment for a multitude of ailments, including diarrhea. However, findings fro...

U.S. FDA approves Larotrectinib, the first TRK inh…

The U.S. Food and Drug Administration (FDA) has approved larotrectinib, the first oral TRK inhibitor, under the brand name Vitrakvi®. The approval is for the treatment of...

Bristol-Myers Squibb awards "Golden Tickets…

Bristol-Myers Squibb Company (NYSE: BMY) and LabCentral, an innovative, shared laboratory space designed as a launchpad for life-sciences and biotech startups, today anno...

FDA approves first treatment for Lambert-Eaton mya…

The U.S. Food and Drug Administration today approved Firdapse (amifampridine) tablets for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults. LEMS is a r...

Alcon to highlight its vision, strategy and benefi…

Alcon, the eye care division of Novartis, will today hold its first Capital Markets Day for investors and analysts in relation to the previously-announced intention of No...

Scorpion venom to shuttle drugs into the brain

The Peptides and Proteins lab at the Institute for Research in Biomedicine (IRB Barcelona) has published a paper in Chemical Communications describing the capacity of a s...