Objective: This study aimed to assess the naturally occurring levels and variation in plasma fatty acids (FA) and ceramide metabolism in healthy volunteers (HV) and patients with Parkinson’s disease (PWPD).

Background: Alpha-synuclein (αSyn) plays a major role in PD. Inhibition of stearyl-CoA desaturase (SCD) reduces mono-unsaturated C16 and C18 FA levels, which are involved in αSyn toxicity in vitro[1,2] and in vivo[3,4]. Preclinically, the ratio of unsaturated to saturated FA (fatty acid desaturase index, FA-DI) in plasma after SCD inhibition correlates strongly with effects on FA-DI in brain, so that the plasma FA-DI may be used as a surrogate for drug-induced changes in brain FA-DI[4]. Furthermore, there appears to be an inverse relationship between glucocerebrosidase (GCase) and αSyn, and even patients with sporadic PD have decreased GCase activity[5,6]. FA-DI and GCase activity may be relevant biomarkers for the effects of SCD inhibitors that are being developed for synucleinopathies. However the inter- and intraday variation in PWPD and HV is unknown.

Method: Ten PWPD (54 –73 yrs) and ten age-matched HV were included. On 3 consecutive days, FA, GCase activity and glucosylsphingosine (GluSph) concentrations were measured throughout the day. Outcomes are expressed as Least Square Means of the difference [95%CI].

Results: There was no statistically significant difference in mean C16 and C18 FA-DI between HV and PWPD. C16 and C18 ratios were relatively stable both within and between days during the study period. The inter-subject variability for the C16 FA-DI was higher in PWPD (37.7%) compared with HV (20.7%), and comparable for C18 FADI. Statistically significant differences (not corrected for multiple testing) between HV and PWPD were found in plasma concentrations of C18:0 (-46.1 ng/mL [-86.9;-5.2]) and C18:1n7 (-11.5 ng/mL [-22.1;-0.8]), as well as plasma proportion of C20:2n6 (0.01% [0.00;0.01]. GCase concentration was higher in PWPD (3.8 µmol/L [0.6;7.1]).

Conclusion: The observed concentrations and variability of fatty acids in HV and PWPD support C16 and C18 FA-DI as suitable biomarkers to demonstrate target engagement of SCD inhibitors in HV and PWPD. The observed difference in GCase activity in this study is not in line with previous reports and may be due to the small sample size.

References: 1. Vincent BM, Tardiff DF, Piotrowski JS, et al. Inhibiting Stearoyl-CoA Desaturase Ameliorates α-Synuclein Cytotoxicity. Cell Rep. 2018;25(10):2742-2754.e31. doi:10.1016/j.celrep.2018.11.028 2. Fanning S, Haque A, Imberdis T, et al. Lipidomic Analysis of α-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Mol Cell. 2019;73(5):1001-1014.e8. doi:10.1016/j.molcel.2018.11.028 3. Nuber S et al., A Stearoyl-Coenzyme A Desaturase Inhibitor Prevents Multiple Parkinson Disease Phenotypes in a-Synuclein Mice. Ann Neurol. 2021; 89(1):74-90. 4. Tardiff D. (2021, March X). A Clinical Stage Stearoyl-CoA Desaturase Inhibitor for Parkinson’s Disease Improves Behavioral and Pathological Features in an a-Synuclein Mouse Model [Conference presentation abstract]. The 15th Annual International Conference on Alzheimer’s and Parkinson’s Diseases (AD/PD™ 2021) Virtual Conference, March 9 to 14, 2021. 5. Mazzulli JR, Xu Y-H, Sun Y, et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011;146(1):37-52. doi:10.1016/j.cell.2011.06.001 6. Gündner AL, Duran-Pacheco G, Zimmermann S, et al. Path mediation analysis reveals GBA impacts Lewy body disease status by increasing α-synuclein levels. Neurobiol Dis. 2019;121:205-213. doi:10.1016/j.nbd.2018.09.015

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