A non-canonical lipid droplet metabolism regulates the conversion of alpha-Synuclein to proteolytic resistant forms in neurons of a<i>Drosophila</i>model of Parkinson disease

Girard, Victor; Jollivet, Florence; Knittelfelder, Oskar; Arsac, Jean-Noël; Chatelain, Gilles; Brink, Daan M. van den; Baron, Thierry; Shevchenko, Andrej; Davoust, Nathalie; Mollereau, Bertrand

doi:10.1101/2020.09.16.299354

Cited by 3 publications

(1 citation statement)

References 90 publications

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“…Interestingly, α-syn binds to LD, a lipid storage organelle contributing to energy metabolism [ 218 , 219 ]. Overexpression of α-syn in neuronal cells induces accumulation of LD which, in turn, increases the amount of proteinase K-resistant forms of α-syn, suggesting a potential pathological role of LD in PD [ 220 ]. Several environmental factors deeply affect lipid homeostasis and, among them, diet plays an important role.…”

Section: Future Directionsmentioning

confidence: 99%

Alpha-Synuclein and Lipids: The Elephant in the Room?

Sarchione

Marchand

Taymans

et al. 2021

Cells

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Since the initial identification of alpha-synuclein (α-syn) at the synapse, numerous studies demonstrated that α-syn is a key player in the etiology of Parkinson’s disease (PD) and other synucleinopathies. Recent advances underline interactions between α-syn and lipids that also participate in α-syn misfolding and aggregation. In addition, increasing evidence demonstrates that α-syn plays a major role in different steps of synaptic exocytosis. Thus, we reviewed literature showing (1) the interplay among α-syn, lipids, and lipid membranes; (2) advances of α-syn synaptic functions in exocytosis. These data underscore a fundamental role of α-syn/lipid interplay that also contributes to synaptic defects in PD. The importance of lipids in PD is further highlighted by data showing the impact of α-syn on lipid metabolism, modulation of α-syn levels by lipids, as well as the identification of genetic determinants involved in lipid homeostasis associated with α-syn pathologies. While questions still remain, these recent developments open the way to new therapeutic strategies for PD and related disorders including some based on modulating synaptic functions.

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Section: Future Directionsmentioning

confidence: 99%

Alpha-Synuclein and Lipids: The Elephant in the Room?

Sarchione

Marchand

Taymans

et al. 2021

Cells

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Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain

Melentev

Ryabova

Surina

et al. 2021

IJMS

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Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used Drosophila melanogaster to investigate the consequences of neuronal knockdown of swiss cheese (sws)—the evolutionarily conserved ortholog of human NTE/PNPLA6—in vivo. Adult flies with the knockdown show longevity decline, locomotor and memory deficits, severe neurodegeneration progression in the brain, reactive oxygen species level acceleration, mitochondria abnormalities and lipid droplet accumulation. Our results suggest that SWS/NTE/PNPLA6 dysfunction in neurons induces oxidative stress and lipid metabolism alterations, involving mitochondria dynamics and lipid droplet turnover in neurodegeneration pathogenesis. We propose that there is a complex mechanism in neurological diseases such as hereditary spastic paraplegia, which includes a stress reaction, engaging mitochondria, lipid droplets and endoplasmic reticulum interplay.

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Chronic Exposure to Paraquat Induces Alpha-Synuclein Pathogenic Modifications in Drosophila

Arsac

Sedru

Dartiguelongue

et al. 2021

IJMS

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Parkinson’s disease (PD) is characterized by the progressive accumulation of neuronal intracellular aggregates largely composed of alpha-Synuclein (αSyn) protein. The process of αSyn aggregation is induced during aging and enhanced by environmental stresses, such as the exposure to pesticides. Paraquat (PQ) is an herbicide which has been widely used in agriculture and associated with PD. PQ is known to cause an increased oxidative stress in exposed individuals but the consequences of such stress on αSyn conformation remains poorly understood. To study αSyn pathogenic modifications in response to PQ, we exposed Drosophila expressing human αSyn to a chronic PQ protocol. We first showed that PQ exposure and αSyn expression synergistically induced fly mortality. The exposure to PQ was also associated with increased levels of total and phosphorylated forms of αSyn in the Drosophila brain. Interestingly, PQ increased the detection of soluble αSyn in highly denaturating buffer but did not increase αSyn resistance to proteinase K digestion. These results suggest that PQ induces the accumulation of toxic soluble and misfolded forms of αSyn but that these toxic forms do not form fibrils or aggregates that are detected by the proteinase K assay. Collectively, our results demonstrate that Drosophila can be used to study the effect of PQ or other environmental neurotoxins on αSyn driven pathology.

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A non-canonical lipid droplet metabolism regulates the conversion of alpha-Synuclein to proteolytic resistant forms in neurons of aDrosophilamodel of Parkinson disease

Cited by 3 publications

References 90 publications

Alpha-Synuclein and Lipids: The Elephant in the Room?

Alpha-Synuclein and Lipids: The Elephant in the Room?

Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain

Chronic Exposure to Paraquat Induces Alpha-Synuclein Pathogenic Modifications in Drosophila

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