Objective: To investigate the association between lipid metabolism and synaptic function in Parkinson’s disease (PD) due to PLA2G6 mutations.

Background: The nervous system is enriched in lipids and contains a more diverse lipid composition than other tissues to maintain neuronal functions. The lipid composition affects synaptic function, but the underlying mechanisms in PD are insufficiently understood. PLA2G6has been isolated as the gene responsible for an autosomal recessive form of PD linked to thePARK14locus. Here, we used a Drosophilamodel of PARK14 for investigation of the mechanisms of PD.

Method: We generated Drosophila PLA2G6(CG6718) –null flies by CRISPR/Cas9 technology and we examined the larval neuromuscular junctions to evaluate neuronal synaptic function. We also analyzed the lipid composition in theDrosophila brain by using Electrospray Ionization-Mass Spectrometry.

Results: Ultrastructure of the synaptic vesicles at the active zone in larval motor neurons showed that synaptic vesicles (SV) diameter in PLA2G6–null larvae was smaller than in control. Furthermore, SV density near the active zone of PLA2G6–null flies was higher than control. Spontaneous neuronal activity, assessed by miniature excitatory junction potential was decreased in PLA2G6–null flies. Measurement of brain lipid composition revealed that increased the proportion of phospholipids with short acyl chain in PLA2G6–null flies.

Conclusion: This study revealed that a Drosophila model ofPARK14had abnormal SV morphology and function. Alteration of lipid composition might cause these abnormalities. The findings indicate that the manipulation of phospholipids in brain might be useful treatment for SV dysfunction in PARK14.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/synaptic-dysfuncion-in-a-drosophila-model-of-park14/