High expression of α-synuclein in damaged mitochondria with PLA2G6 dysfunction

Abstract

To clarify the role of α-synuclein (αSyn) in neuronal membrane remodeling, we analyzed the expression of αSyn in neurons with a dysfunction of PLA2G6, which is indispensable for membrane remodeling. αSyn/phosphorylated-αSyn (PαSyn) distribution and neurodegeneration were quantitatively estimated in PLA2G6-knockout (KO) mice, which demonstrate marked mitochondrial membrane degeneration. We also assessed the relationship between αSyn deposits and mitochondria in brain tissue from patients with PLA2G6-associated neurodegeneration (PLAN) and Parkinson’s disease (PD), and quantitatively examined Lewy bodies (LBs) and neurons. The expression level of αSyn was elevated in PLA2G6-knockdown cells and KO mouse neurons. Strong PαSyn expression was observed in neuronal granules in KO mice before onset of motor symptoms. The granules were mitochondrial outer membrane protein (TOM20)-positive. Ultramicroscopy revealed that PαSyn-positive granules were localized to mitochondria with degenerated inner membranes. After symptom onset, TOM20-positive granules were frequently found in ubiquitinated spheroids, where PαSyn expression was low. Axons were atrophic, but the neuronal loss was not evident in KO mice. In PLAN neurons, small PαSyn-positive inclusions with a TOM20-positive edge were frequently observed and clustered into LBs. The surfaces of most LBs were TOM20-positive in PLAN and TOM20-negative in PD brains. The high proportion of LB-bearing neurons and the preserved neuronal number in PLAN suggested long-term survival of LB-bearing neurons. Elevated expression of αSyn/PαSyn in mitochondria appears to be the early response to PLA2G6-deficiency in neurons. The strong affinity of αSyn for damaged mitochondrial membranes may promote membrane stabilization of mitochondria and neuronal survival in neurons.

Mitochondrial dysfunction in Parkinson’s disease

“…In PLA2G6 knockout mice, abnormal mitochondria with multiple morphological changes are presented in the anterior horns spinal cord [ 107 ]. Most interestingly, in PLA2G6 knockout mice as well as PLA2G6 knockdown cells, α-syn levels are increased [ 108 ]. The immunoreactivity of S129-site phosphorylated α-syn is strongly presented in neuronal granules which are labeled with mitochondrial outer membrane 20 kDa protein (TOM20) in PLA2G6 knockout mice [ 108 ], suggesting an accumulation of α-syn on damaged mitochondria.…”

“…Most interestingly, in PLA2G6 knockout mice as well as PLA2G6 knockdown cells, α-syn levels are increased [ 108 ]. The immunoreactivity of S129-site phosphorylated α-syn is strongly presented in neuronal granules which are labeled with mitochondrial outer membrane 20 kDa protein (TOM20) in PLA2G6 knockout mice [ 108 ], suggesting an accumulation of α-syn on damaged mitochondria. In PLAN brains, α-syn labeled small inclusions are colocalized with TOM20, which may develop to LBs [ 108 ], further suggesting a role of PLA2G6 in mitochondrial dysfunction and LB formation.…”

iPLA2β and its role in male fertility, neurological disorders, metabolic disorders, and inflammation

“…In iPLA 2 β-null mice decreased brain docoshexaenoic acid metabolism and signaling have been observed that may play a role in neuronal dysfunction 58,59 . It has also been suggested that neuroaxonal dystrophy in iPLA 2 β deficiency results from insufficient remodeling and degeneration of mitochondrial and presynaptic membranes 60 , and there is evidence of mitochondrial injury and dysfunction in iPLA 2 β-null mice 61,62 and of increased mitochondrial lipid peroxidation and dysfunction in brains of iPLA 2 β-null Drosophila and in fibroblasts of human subjects with iPLA 2 β gene mutations that cause INAD 63 . iPLA 2 β PARK14 mutants are also defective in preventing rotenone-induced mitochondrial dysfunction, generation of reactive oxygen species, and activation of the mitochondrial apoptotic pathway under conditions where WT iPLA 2 β does prevent these events 64 .…”

Mitochondria: A Common Target for Genetic Mutations and Environmental Toxicants in Parkinson’s Disease

“…Although the pathological mechanism of PLA2G6 remains elusive, it has been suggested to affect lipid homeostasis and metabolism as well as impact mitochondrial membranes ( Beck et al, 2011 ). Further, PLA2G6 knockout mice displayed degenerated mitochondrial membranes and elevated levels of synuclein ( Sumi-Akamaru et al, 2016 ). PLA2G6 has been reported to be immunopositive in the Lewy bodies of idiopathic PD, suggesting its pathogenic role extends beyond familial PD ( Miki et al, 2017 ).…”