Abstract by Jesper Elmsted Dreier

Parkinson’s disease(PD) is the second most common neurodegenerative disease and has been diagnosed for more than a  century. Yet, there is still no cure for PD despite extensive efforts from the scientific community. Furthermore, the pathological mechanism is still unclear. However, it is evident that both the protein, α-synuclein(αS) and lipids play a role. This work focuses on the lipid changes in the brain of PD patients, their interaction with αS, how they contribute to the aggregation of αS, and potential therapeutic strategies.

The lipids in the PD brain are investigated using shotgun mass-spectrometry on lipids extracted from post-mortem brain samples. We analysed samples from healthy controls and individuals with both sporadic PD(sPD) and PD with mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase(GCase), which is the biggest genetic risk factor for PD. Furthermore, we analysed samples from different brain regions to asses whether the lipidome changes are equal or varies between regions. The largest changes to the lipidome were detected in the amygdala of cases with sPD with a long disease duration and in the locus coeruleus, cingulate cortex, and amygdala of cases with PD-GBA risk mutations. We observed significant correlations between many different lipid classes and GCase activity, suggesting a lipidome-wide effect of GBA1 mutations. The correlations often showed a threshold-dependent pattern rather than a linear relationship.

The abundances of sphingolipids(SL) were significantly perturbed across brain regions in the lipidomic analyses. In addition, GCase is involved in the metabolism of SLs. We thus wanted to investigate the effect of SLs in the pathogenesis of PD. Using in-vitro aggregation assays, we found that gluco-SLs significantly accelerates αS aggregation. Single-chain SLs accelerated the aggregation, no matter the SL class. Investigating the lipid-αS interaction, we find that the affinity between the SLs and αS is low, despite the large effect on aggregation.

Finally, we investigated inhibition of the lipid-induced aggregation of αS. We found that ambroxol(ABX), a small-molecule chaperone known to stabilize GCase, also directly inhibits αS–lipid coaggregation by targeting the primary nucleation step. Specifically, we show that ABX displaces αS from negatively charged membranes and prevents the formation of early coaggregates, highlighting its therapeutic potential in PD and related synucleinopathies.

Taken together, we find that the abundance of lipid classes and the distribution of species are perturbed in the PD brain. SLs, that we saw affected in the brain samples, can accelerate αS aggregation. Lastly, ABX can inhibit the lipid-induced aggregation.