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.
Highlights
It is well known that α-synuclein is a pathological marker of Parkinson disease (PD), because αSyn/phosphorylated αSyn (PαSyn) is a main component of Lewy bodies (LBs)
In Pla2g6-KO mice at the pre-clinical stage (15 weeks), the immunoreactivity of αSyn was highly diffuse in the gray matter (Fig. 2b). αSyn staining in the neuropil had a punctate pattern, similar to that in wild-type mice, but the cytoplasm of some swollen neurons was mildly positive for αSyn (Fig. 2c)
Prominent accumulation of PαSyn in damaged mitochondria was shown in Pla2g6-KO mice, which constitute a model of PLA2G6-associated neurodegeneration (PLAN)
Summary
It is well known that α-synuclein (αSyn) is a pathological marker of Parkinson disease (PD), because αSyn/phosphorylated αSyn (PαSyn) is a main component of Lewy bodies (LBs). The physiological function of αSyn has recently become known. ΑSyn localizes to nuclei and subcellular organelles, including mitochondria and mitochondrion-associated endoplasmic reticulum (ER) membranes [5, 16, 37]. ΑSyn binds to lipid membranes [42, 43], in particular, to membranes with high. Mitochondria have various functions, including oxidative phosphorylation, lipid metabolism, endocytosis [24], apoptosis, and calcium and iron homeostasis [32]. A mitochondrial inner membrane-specific phospholipid, cardiolipin, is crucial for the integrity and function of mitochondria [25, 32]. In the brains of mice lacking αSyn, the mitochondrial lipid composition changes, and complex I/III activity is reduced [12]. The Nterminus of αSyn regulates mitochondrial membrane
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