Lipids and Secretory Vesicle Exocytosis

The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids

“…In addition to acting as building blocks for synaptic vesicles and neuronal plasma membranes, brain lipids are involved in diverse neuronal functions including scaffolding (Lee et al, 2021 ), neurodevelopment (Zhu et al, 2016 ), signalling (Falomir-Lockhart et al, 2019 ), neuroinflammation (Giacobbe et al, 2020 ), neurometabolism (Bruce et al, 2017 ), and cognition (de Mendoza and Pilon, 2019 ; Derbyshire, 2018 ; Egawa et al, 2016 ; Joffre, 2019 ; Snowden et al, 2017 ; Tracey et al, 2018 ). Dynamic regulation of the brain-lipid landscape via the coordinated activity of phospholipases and other enzymes is crucial for mediating appropriate membrane curvature, surface chemistry, fluidity and fusogenicity of the phospholipid membrane bilayer during vesicular trafficking, exocytosis, endocytosis and synaptic plasticity underpinning memory formation (Akefe, 2022 ; Akefe et al, 2023 ; Alrayes et al, 2015 ; Barber and Raben, 2019 ; Bruce et al, 2017 ; Carta et al, 2014 ; Zhu et al, 2016 ). The importance of phospholipases in this process is exemplified in hereditary spastic paraplegia (HSP; Strümpell-Lorrain disease) in which a mutation in the DDHD2 gene of phospholipase A1 (PLA1) is associated with neuromuscular and cognitive dysfunction (Akefe, 2022 ; Alrayes et al, 2015 ; Inloes et al, 2014 ; Joensuu et al, 2020b ; Murala et al, 2021 ), autism (Matoba et al, 2020 ), schizophrenia (Park et al, 2021 ), intellectual disability (Alrayes et al, 2015 ), and mental retardation (Alrayes et al, 2015 ; Darios et al, 2020 ; Inloes et al, 2014 ; Joensuu et al, 2020b ).…”

“…During neurological processes such as neurotransmitter release, long-term potentiation and subsequent synaptic plasticity, the targeted activity of phospholipases plays a key role by catalysing the hydrolysis of phospholipids to generate FFAs thereby changing the local environment of the targeted bilayer (Akefe et al, 2023 ; Joensuu et al, 2020b ; Puchkov and Haucke, 2013 ) and consequently impacting neurotransmission (Goldschmidt et al, 2016 ). Phospholipase A2 (PLA2) hydrolyses the fatty acyl chain on the sn-2 position of canonical phospholipids to generate unsaturated FFAs such as AA, which further initiate a cascade of bioactive signalling molecules in many biological systems including neuroinflammation, neurotransmitter release and long-term potentiation (Higgs and Glomset, 1996 ; Inloes et al, 2014 ).…”