The Role of Neutral Sphingolipids in the Pathogenesis of Parkinson Disease and Dementia with Lewy Bodies

The molecular mechanisms underlying the association between mutations in GBA1 and risk of developing the 'synucleinopathy' disorders Parkinson's disease (PD) and dementia with Lewy bodies (DLB) remain elusive. To better understand the precise molecular cascade that connects GBA1 mutations with α-synuclein dysregulation, a modified lipid extraction and HPTLC protocol was optimized to detect changes in levels of neutral sphingolipids (SLs) from neural cells and tissue expressing wild-type (WT) GBA1, mutant GBA1, or both. We demonstrate that mutant GBA1 does not confer a dominant-negative effect on WT GBA1-mediated activity; however, bona fide loss-of-enzymatic function mutation events led to the accumulation of lipid substrates in neural cells and tissue, and enhance α- synuclein/ubiquitin reactivity in brain tissue of mutant gba1 mice. Our HPLC-MS/MS data are consistent with other studies demonstrating that heterozygous GBA1 mutations do not lead to lipid accumulation, but may alter α-synuclein degradation through a yet-to-be defined novel gain-of-toxic function event.