Lipid droplets as Ying-Yang markers of neurodegeneration in models of synucleinopathies

Abstract

Alpha-synuclein (aSyn) pathology is a hallmark in the onset and progression of several synucleinopathies, including Parkinson’s disease. It has been demonstrated that lipid disturbances are associated with aSyn pathology. Our aim was to study neutral lipid metabolism in several in vivo and in vitro models of aSyn accumulation. To this end, different forms of aSyn overexpressed in neurons and toxicant-induced animal models related with synucleinopathies were used. In neuronal cultures, we demonstrated that the overexpression of aSyn (WT and mutant A53T) induced the accumulation of lipid droplets (LD) and free cholesterol (p<0.01). We found that LD biogenesis is a “hormesis mechanism” for preventing neuronal death induced by proteostasis impairment. Neuron-glia crosstalk was evaluated using neuronal secretomes, demonstrating that WT and A53T neurons exacerbated LD accumulation in glial cells. Moreover, the pesticide maneb triggered ferroptosis associated with aSyn overexpression in neurons with a rise in neutral lipid content (p<0.05). These results suggest that altered lipidostasis could be a hallmark of early aSyn-induced neurodegeneration. Mice exposed to neurotoxicants, as maneb and iron overload, showed aSyn upregulation (p<0.05) in whole brain and midbrain associated with motor impairment. In addition, the loss of tyrosine hydroxylase neurons in midbrain (p<0.001) was related to ferroptosis markers. Midbrain lipid profiles revealed that injured mice presented lipolysis as a consequence of diminished neutral lipid acylation (p<0.01) and lipogenesis, and higher cholesteryl ester deacylation rendering cholesterol accumulation (p<0.05). Neuronal death and movement disorders are linked with active lipolysis in in vivo models. Thus, indicating that marked injury in synucleinopathies is accompanied by impaired LD formation with cholesterol accumulation. Taken together, our results postulate LD as ying/yang markers of different stages of aSyn-induced neurodegeneration