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

To clarify the role of alpha-synuclein (alpha Syn) in neuronal membrane remodeling, we analyzed the expression of alpha Syn in neurons with a dysfunction of PLA2G6, which is indispensable for membrane remodeling. alpha Syn/phosphorylated-alpha Syn (P alpha Syn) distribution and neurodegeneration were quantitatively estimated in PLA2G6-knockout (KO) mice, which demonstrate marked mitochondrial membrane degeneration. We also assessed the relationship between alpha Syn 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 alpha Syn was elevated in PLA2G6-knockdown cells and KO mouse neurons. Strong P alpha Syn 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 P alpha Syn-positive granules were localized to mitochondria with degenerated inner membranes. After symptom onset, TOM20-positive granules were frequently found in ubiquitinated spheroids, where P alpha Syn expression was low. Axons were atrophic, but the neuronal loss was not evident in KO mice. In PLAN neurons, small P alpha Syn-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 alpha Syn/P alpha Syn in mitochondria appears to be the early response to PLA2G6-deficiency in neurons. The strong affinity of alpha Syn for damaged mitochondrial membranes may promote membrane stabilization of mitochondria and neuronal survival in neurons.