Abstract
α-synuclein (α-syn) accumulation and aggregation is a common pathological factor found in synucleinopathies, a group of neurodegenerative disorders that includes Parkinson´s disease (PD). It has been proposed that lipid dyshomeostasis is responsible for the occurrence of PD-related processes, however, the precise role of lipids in the onset and progression of neurodegenerative disorders remains unclear. Our aim was to investigate the effect of α-syn overexpression on neutral lipid metabolism and how this impacts on neuronal fate. We found lipid droplet (LD) accumulation in cells overexpressing α-syn to be associated with a rise in triacylglycerol (TAG) and cholesteryl ester (CE) levels. α-syn overexpression promoted diacylglycerol acyltransferase 2 upregulation and acyl-CoA synthetase activation, triggering TAG buildup, that was accompanied by an increase in diacylglycerol acylation. Moreover, the CE increment was associated with higher activity of acyl-CoA:cholesterol acyltransferase. Interestingly, α-syn overexpression increased cholesterol lysosomal accumulation. We observed that sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 were differentially regulated by α-syn overexpression. The latter gave rise to a reduction in SREBP-1 nuclear translocation and consequently in fatty acid synthase expression, whereas it produced an increase in SREBP-2 nuclear localization. Surprisingly, and despite increased cholesterol levels, SREBP-2 downstream genes related to cholesterolgenesis were not upregulated as expected. Notably, phospholipid (PL) levels were diminished in cells overexpressing α-syn. This decrease was related to the activation of phospholipase A2 (PLA2) with a concomitant imbalance of the PL deacylation-acylation cycle. Fatty acids released from PLs by iPLA2 and cPLA2 action were esterified into TAGs, thus promoting a biological response to α-syn overexpression with uncompromised cell viability. When the described steady-state was disturbed under conditions favoring higher levels of α-syn, the response was an enhanced LD accumulation, this imbalance ultimately leading to neuronal death.
Highlights
The biology of α-synuclein (α-syn) has attracted a great deal of interest since the association of this protein with a group of devastating neurodegenerative disorders named synucleinopathies, the most prevalent of which is Parkinson’s disease (PD)
wild type (WT) α-syn overexpression alters cellular lipid homeostasis Our lab has previously established that PD-related insults, such as iron overload and overexpression of A53T α-syn mutant, shift neuronal lipid metabolism towards lipid droplet (LD) accumulation[30,49]
In order to further characterize the mechanisms involved in α-syn-induced LD accumulation, we studied the status of the master regulators of lipid homeostasis: sterol regulatory element-binding protein (SREBP)-1 and SREBP-2
Summary
The biology of α-synuclein (α-syn) has attracted a great deal of interest since the association of this protein with a group of devastating neurodegenerative disorders named synucleinopathies, the most prevalent of which is Parkinson’s disease (PD). Several structural biology studies demonstrate that α-syn has affinity for different kinds of lipids such as Official journal of the Cell Death Differentiation Association. SNCA knock-out mice displayed altered polyunsaturated FA metabolism, with lower uptake of arachidonic acid observed in neurons and astrocytes and increased acylation of docosahexaenoic acid in PLs21. These findings shed light on adaptive responses triggered by α-syn silencing and highlight the role of the protein in FA turnover in the brain. Overexpression of α-syn triggers different cellular responses related to lipid metabolism and signaling.
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