Cerebrospinal Fluid Profiles in Parkinson’s Disease: No Accumulation of Glucosylceramide, but Significant Downregulation of Active Complement C5 Fragment

Article type: Research Article

Authors: Niimi, Yoshiki^a | Mizutani, Yasuaki^a | Akiyama, Hisako^c | Watanabe, Hirohisa^a | Shiroki, Ryoichi^b | Hirabayashi, Yoshio^d | Hoshinaga, Kiyotaka^b | Mutoh, Tatsuro^{a; *}

Affiliations: [a] Department of Neurology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan | [b] Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan | [c] RIKEN Center for Brain Science, Wako, Saitama, Japan | [d] RIKEN Cluster for Pioneering Research, RIKEN, Wako, Saitama, Japan

Correspondence: [*] Correspondence to: Dr. Tatsuro Mutoh, MD, PhD, Department of Neurology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake-City, Aichi 470-1192, Japan. Tel.: +81 562 93 9295; Fax: +81 562 93 1856; E-mail: [email protected].

Abstract: Background:As mutations in glucocerebrosidase 1 (GBA1) are a major risk factor for Parkinson’s disease (PD), decreased GBA1 activity might play an important role in the pathogenesis of the disease. However, there are currently no reports on glucosylceramide levels in the cerebrospinal fluid (CSF) in PD. Objective:We investigated whether glucosylceramide accumulation and abnormal immune status in the brain are associated with PD. Methods:We measured glucosylceramide by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) as well as levels of the active fragment of complement C5, C5a, in the CSF of 33 PD, 15 amyotrophic lateral sclerosis (ALS) and 22 neurologically normal control (NNC) subjects. Serum C5a levels in all PD and ALS cases and in a limited number of NNC subjects (n = 8) were also measured. Results:C5a levels in CSF were significantly downregulated in PD compared with NNC. Moreover, CSF C5a/serum C5a ratio showed pronounced perturbations in PD and ALS patients. LC-ESI-MS/MS revealed a statistically significant accumulation of a specific subspecies of glucosylceramide (d18 : 1/C23 : 0 acyl chain fatty acid) in ALS, but not in PD. Interestingly, CSF glucosylceramide (d18 : 1/C23 : 0) exhibited a significant correlation with CSF C5a levels in PD, but not ALS. No correlation was observed between C5a levels or glucosylceramide subspecies content and disease duration, levodopa equivalent daily dose or Hoehn & Yahr staging in PD. Conclusion:Our findings demonstrate complement dysregulation without glucosylceramide accumulation in PD CSF. Furthermore, we found an association between a specific glucosylceramide subspecies and immune status in PD.

Keywords: Parkinson’s disease, complement, mass spectrometry, innate immunity, glycosphingolipids

DOI: 10.3233/JPD-202310

Journal: Journal of Parkinson's Disease, vol. 11, no. 1, pp. 221-232, 2021