Parkinson’s disease-associated iPLA2-VIA/ PLA2G6 regulates neuronal functions and α-synuclein stability through membrane remodeling

Abstract

Mutations in the iPLA2-VIA/PLA2G6 gene are responsible for PARK14-linked Parkinson’s disease (PD) with α-synucleinopathy. However, it is unclear how iPLA2-VIA mutations lead to α-synuclein (α-Syn) aggregation and dopaminergic (DA) neurodegeneration. Here, we report that iPLA2-VIA–deficient Drosophila exhibits defects in neurotransmission during early developmental stages and progressive cell loss throughout the brain, including degeneration of the DA neurons. Lipid analysis of brain tissues reveals that the acyl-chain length of phospholipids is shortened by iPLA2-VIA loss, which causes endoplasmic reticulum (ER) stress through membrane lipid disequilibrium. The introduction of wild-type human iPLA2-VIA or the mitochondria–ER contact site-resident protein C19orf12 in iPLA2-VIA–deficient flies rescues the phenotypes associated with altered lipid composition, ER stress, and DA neurodegeneration, whereas the introduction of a disease-associated missense mutant, iPLA2-VIA A80T, fails to suppress these phenotypes. The acceleration of α-Syn aggregation by iPLA2-VIA loss is suppressed by the administration of linoleic acid, correcting the brain lipid composition. Our findings suggest that membrane remodeling by iPLA2-VIA is required for the survival of DA neurons and α-Syn stability.

Apitherapy for Parkinson’s Disease: A Focus on the Effects of Propolis and Royal Jelly

“…It is now well-known that altered gut microbiome is a major contributor to the initiation and development of PD pathology [ 10 , 11 , 121 ]. Evolving knowledge implies that dietary interventions such as fatty acids (phospholipid membrane precursors), amino acids, and microbiota-directed therapy (e.g., probiotics, prebiotics, and postbiotics) may correct gut alterations, treat GI symptom, and promote CNS functioning in PD [ 10 , 18 , 121 , 122 ]. Propolis and RJ are rich in amino acids, fatty acids, and phospholipids [ 28 , 37 , 41 , 55 ].…”

“…These molecules induce mutations in genes involved in lipid metabolism in the brain such as iPLA2-VIA resulting in dysregulations in the metabolism of fatty acids through a mechanism that involves shortening of acyl-chain in phospholipids, which interferes with mitochondrial functioning, homeostasis, structure of synaptic vesicles, and neurotransmission in the endoplasmic reticulum resulting in high loss of dopaminergic neurons. In addition, depletion of iPLA2-VIA is associated with loss of α -synuclein affinity for phospholipids with shorter fatty acyl chains evoking increases in α -synuclein accumulation, neuroinflammation, migration of reactive microglia into the pathological region, barrier leakage, and reduction of immune cells infiltration into the SNC leading to increased α -synuclein accumulation in neurons and further apoptosis and cell death due to activation of apoptotic signaling cascade involving c-Jun N-terminal kinases and its downstream effector, caspase-3 [ 4 , 18 ].…”

“…α -Synuclein then moves through the vagus nerve to be seeded in vulnerable neurons in the CNS [ 9 – 11 ]. In the meantime, the expression of genes involved in the synthesis of phospholipids of the biomembrane such as iPLA2-VIA decreases whereas microglia and astrocytes get activated and migrate in response to inflammation and auto-oxidation of dopamine, which trigger the expression of pathological genes such as α -synuclein and parkin [ 18 ]. As a result, α -synuclein pathology increases causing a widespread of initial seeds of α -synuclein to the vulnerable neighboring neurons.…”

A course-based undergraduate research experience examining neurodegeneration in Drosophila melanogaster teaches students to think, communicate, and perform like scientists

“…Experimental results may point to a prominent contribution of cholinergic neurons to the etiology of PLAN, which is somewhat unexpected given that motor decline in Parkinson's disease has been attributed primarily to the loss of dopaminergic neurons [41]. Indeed, recent experimental PLAN models have focused on dopaminergic neuron loss in mouse, zebrafish, and Drosophila [42][43][44]. Still, human PLAN patients display degeneration in multiple brain areas, and a role for cholinergic neurons in Parkinson's is beginning to be investigated [20,41].…”

In Vivo Mitochondrial Function in Idiopathic and Genetic Parkinson’s Disease

“…Similar impairments in the phospholipidic membrane were also noticed in PINK1+ patients even if those patients showed energetics impairments. This suggests that there might be a sort of connection between membrane deterioration and genetic mutations linked to PD and a potential link between phospholipidic membranes impairments and mitochondria function [42][43][44]. In this respect, further analyses are needed.…”