Biology subjects

Dreier, J. E.

Publications and source records attributed to Dreier, J. E..

3 recordsLinked to original sources

bioRxiv2025

Ambroxol displaces α-synuclein from the membrane and inhibits the formation of early protein-lipid coaggregates

Parkinsons disease (PD) is a neurological disorder characterized by neuronal loss and the deposition of -synuclein-lipid coaggregates in the brain of patients as well as disruptions in lipid metabolism. Mutations in the gene GBA, which encodes the lysosomal glycoprotein Glucocerebrosidase, are together the most important genetic risk factor for PD and have been associated with lysosomal dysfunction, accumulation of pathological -synuclein as well as major changes in both the levels and properties of lipids. Ambroxol, a small molecule chaperone capable of binding and stabilizing Glucocerebrosidase, was found to revert changes in lipid levels and increase in -synuclein levels due to GBA mutations potentially via restoring lysosomal function. Here, we show that Ambroxol also has a direct effect on -synuclein-lipid co-aggregation by inhibiting the primary nucleation step in the aggregation process. We find that Ambroxol not only displaces -synuclein from negatively charged membranes but also prevents the formation of early -synuclein-lipid coaggregates during primary nucleation. These results suggest that Ambroxol may have beneficial effects on other synucleinopathies, such as multiple system atrophy and dementia with Lewy Bodies, that are also characterised by the aggregation of -synuclein into amyloid fibrils.

biophysics↗

bioRxiv2024

Lipidomic Profiling Reveals Shared and Distinct Pathological Signatures in Sporadic Parkinson's Disease and GBA Mutation Carriers: Implications for Disease Mechanisms

Parkinsons Disease (PD) is a neurodegenerative disorder characterised by the deposition of protein-lipid inclusions, containing alpha-synuclein, neuronal cell loss and disruptions in lipid metabolism such as those associated with GBA mutations. GBA mutations are together an important genetic risk factor for PD and are associated with a decrease in glucocerebrosidase, a lysosomal glycoprotein encoded by GBA, increase in alpha-synuclein and changes in sphingolipids levels and composition. However, the extent of lipid metabolism disruptions associated to PD and their contributions to disease progression remain unclear. In this study, we used a combination of biochemical and lipidomic analyses of amygdala from healthy controls (HC) and people with sporadic (sPD) or GBA-associated PD (PD-GBA) to investigate the correlation between alpha-synuclein, glucocerebrosidase and lipids. We found extensive metabolic remodelling of brain lipids, including increased free cholesterol, diacylglycerides, sphingolipids and specific glycerophospholipids in amygdala from people with sPD and disease duration above 30 years (sPD>30y) and from people with PD carriers of a GBA risk mutation (PD-GBArisk) relative to HC. The levels of free cholesterol, diacylglycerides, sphingolipids and specific glycerophospholipids all correlated positively with pathological S and negatively with GCase activity. In contrast, the levels of phosphatidylethanolamine and cardiolipin only correlated positively with GCase activity. Moreover, we observed changes in the distribution of species for sphingolipids and glycerophospholipids in opposite directions for two categories of PD cases. We found a shift from short to long sphingomyelin and ceramide and from long to short phosphatidylserine and phosphatidylethanolamine in sPD>30y and PD-GBArisk cases and the opposite in sPD<10y and PD-GBAsevere cases. The relative proportion of lipid species affected in these samples all correlated with glucocerebrosidase activity and pathological alpha-synuclein levels. Together, these findings highlight the correlation between glucocerebrosidase, pathological alpha-synuclein and lipid levels in PD. Moreover, the identified opposite changes in lipid distribution for two categories of people with sPD and PD-GBA underscore the importance of patient stratification in clinical trials aiming at reverting PD-related lipid changes.

neuroscience↗

bioRxiv2023

Lipid levels correlate with neuronal and dopaminergic markers during the differentiation of SH-SY5Y cells

Parkinsons Disease (PD) is characterized by the loss of dopaminergic neurons and the deposition in the remaining cells of protein inclusions called Lewy Bodies (LBs). LBs are heterogeneous structures composed of protein and lipid molecules and their main constituent is the presynaptic protein -synuclein. SH-SY5Y cells are neuroblastoma cells commonly used to model PD because they express dopaminergic markers and -synuclein and they can be differentiated into neuronal cells using established protocols. Despite increasing evidence pointing towards a role of lipids in the initiation of PD, limited knowledge is available on the lipidome of undifferentiated and differentiated SH-SY5Y cells. In this study, we show that the levels and chemical properties of negatively charged phospholipids, diacyl glycerol and sphingolipids are specifically altered along the differentiation process of SH-SY5Y cells and that the levels of these lipids species correlate with those of dopaminergic and neuronal markers. These results are supported by proteomic data showing that the main biological processes affected by the differentiation of SH-SY5Y cells are lipid metabolism and processes associated with neuron maturation. Finally, our results show that electrophysiological activity can be detected in differentiated SH-SY5Y cells at a stage where most of the lipid changes have reached their maximal value. These results provide the first complete and quantitative characterisation of the changes in lipidome associated with the differentiation of SH-SY5Y cells into more neuronal and dopaminergic-like phenotype and serve as a basis for further characterisation of lipid disruptions in association with PD and its risk factors in this dopaminergic-like neuronal cell model.

cell biology↗