Impaired Sphingolipid Hydrolase Activities in Dementia with Lewy Bodies and Multiple System Atrophy

The synucleinopathies are a group of neurodegenerative diseases characterized by the oligomerization of alpha-synuclein protein in neurons or glial cells. Recent studies provide data that ceramide metabolism impairment may play a role in the pathogenesis of synucleinopathies due to its influence on alpha-synuclein accumulation. The aim of the current study was to assess changes in activities of enzymes involved in ceramide metabolism in patients with different synucleinopathies (Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA)). The study enrolled 163 PD, 44 DLB, and 30 MSA patients as well as 159 controls. Glucocerebrosidase, alpha-galactosidase, acid sphingomyelinase enzyme activities, and concentrations of the corresponding substrates (hexosylsphingosine, globotriaosylsphingosine, lysosphingomyelin) were measured by liquid chromatography tandem-mass spectrometry in blood. Expression levels of GBA, GLA, and SMPD1 genes encoding glucoceresobridase, alpha-galactosidase, and acid sphingomyelinase enzymes, correspondently, were analyzed by real-time PCR with TaqMan assay in CD45 + blood cells. Increased hexosylsphingosine concentration was observed in DLB and MSA patients in comparison to PD and controls (p < 0.001) and it was associated with earlier age at onset (AAO) of DLB (p = 0.0008). SMPD1 expression was decreased in MSA compared to controls (p = 0.015). Acid sphingomyelinase activity was decreased in DLB, MSA patients compared to PD patients (p < 0.0001, p < 0.0001, respectively), and in MSA compared to controls (p < 0.0001). Lower acid sphingomyelinase activity was associated with earlier AAO of PD (p = 0.012). Our data support the role of lysosomal dysfunction in the pathogenesis of synucleinopathies, namely, the pronounced alterations of lysosomal activities involved in ceramide metabolism in patients with MSA and DLB.