Could treating Parkinson’s disease be as simple as controlling one’s lipid metabolism? In the September 29 Annals of Neurology online, researchers led by Dennis Selkoe, Brigham and Women’s Hospital, Boston, report that an inhibitor of stearoyl-CoA desaturase reduced α-synuclein inclusions in a mouse model of PD and steadied the animals on their feet.

The enzyme stearoyl-CoA desaturase catalyzes the rate-limiting step in the production of mono-unsaturated fatty acids, including the 18-carbon oleic and the 16-carbon palmitoleic acids. Previous work from Selkoe’s lab suggested that oleic acid increases α-synuclein toxicity and that a small molecule inhibitor of the desaturase, dubbed 5b, protected against this effect in yeast and mammalian neurons (Atkinson et al., 2011; Fanning et al., 2019). Could 5b prevent the motor symptoms of PD?

To find out, first author Silke Nuber and colleagues tested 5b in male 3K mice. Nuber had developed this strain to express human α-synuclein with three lysine mutations—E35K, E46K, and E61K—that destabilize α-synuclein tetramers (Oct 2018 news). Selkoe believes these tetramers are innocuous, while monomers are more likely to aggregate, and that a physiologic ratio between the two must be maintained for synaptic vesicle flux to be healthy (Aug 2011 news).

Nuber starting lacing the mice’s drinking water with compound 5b when they were 10 weeks old, then documented their motor function at 4 ½ and 6 ½ months. These animals typically begin to have trouble coordinating movement at around 12 weeks and deteriorate noticeably at six months. Nuber also tested 5b in mice overexpressing wild-type human α-synuclein, whose gait becomes mildly abnormal with age.

At 4 ½ months, the 5b-treated 3K mice outperformed those on placebo on motor tests, such as climbing poles, hanging by their four limbs from a wire, maintaining their balance on a rotating rod, and their gait improved slightly. By 6 months, the 5b-treated mice were doing significantly better than controls on all those tests, and they fell less often when placed on top a vertical pole. The compound had little effect on mice expressing wild-type human α-synuclein, but it did improve their gait at six months. 

In keeping with previous in vitro work, Nuber and colleagues found that 5b increased the amount of soluble α-synuclein, while decreasing the amount of lipid-associated α-synuclein in extracts of mouse cortex. This was accompanied by a doubling of the α-synuclein tetramer-to-monomer ratio and a halving of insoluble α-synuclein. Dopaminergic fibers from treated mice harbored smaller aggregates, which contained less lipid than aggregates in control mice.

All told, the findings indicate that decreasing monounsaturated fatty acids reduced aggregation of α-synuclein, protected dopaminergic neurons, and prevented progressive motor deficits.

Unfortunately, the mice lost patches of fur and developed a squint. Hair loss and dry eye are known side effects of stearoyl-CoA desaturase inhibition. In particular, palmitoleic acid deficiency has been linked to hair loss. Indeed, Nuber found that 5b decreased the ratio of monounsaturated palmitoleic acid to saturated palmitic acid, indicating that the drug was blocking the desaturase. “These changes thus provide a clear pharmacodynamic readout that the inhibitor was engaging its enzymatic target,” write the authors.

Will these side effects preclude hope of treating PD with such compounds? Yumanity Therapeutics is a biotech company co-founded by the late Susan Lindquist from MIT, who had collaborated with Selkoe on research into how lipids affect α-synuclein. Yumanity completed a Phase 1 single ascending dose study of its stearoyl-CoA-desaturase inhibitor YTX-7739 in healthy volunteers, and is planning subsequent trials in healthy volunteers and people with Parkinson’s. Co-author Ulf Dettmer and Selkoe are paid consultants for Yumanity.—Tom Fagan

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References

News Citations

  1. Sans Synuclein Tetramers, Mice Mimic Parkinson’s Disease
  2. An α-Synuclein Twist—Native Protein a Helical Tetramer

Paper Citations

  1. . N-benzylimidazole carboxamides as potent, orally active stearoylCoA desaturase-1 inhibitors. Bioorg Med Chem Lett. 2011 Mar 15;21(6):1621-5. Epub 2011 Jan 31 PubMed.
  2. . Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Mol Cell. 2019 Mar 7;73(5):1001-1014.e8. Epub 2018 Dec 4 PubMed.

Further Reading

Primary Papers

  1. . A stearoyl-CoA desaturase inhibitor prevents multiple Parkinson's disease-phenotypes in α-synuclein mice. Ann Neurol. 2020 Sep 29; PubMed.