Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A₂β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

Abstract

Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disease characterized by the widespread presence of axonal swellings (spheroids) in the CNS and PNS and is caused by gene abnormality in PLA2G6[calcium-independent phospholipase A 2 ␤ (iPLA 2 ␤)], which is essential for remodeling of membrane phospholipids. To clarify the pathomechanism of INAD, we pathologically analyzed the spinal cords and sciatic nerves of iPLA 2 ␤ knock-out (KO) mice, a model of INAD. At 15 weeks (preclinical stage), periodic acid-Schiff (PAS)-positive granules were frequently observed in proximal axons and the perinuclear space of large neurons, and these were strongly positive for a marker of the mitochondrial outer membrane and negative for a marker of the inner membrane. By 100 weeks (late clinical stage), PAS-positive granules and spheroids had increased significantly in the distal parts of axons, and ultrastructural examination revealed that these granules were, in fact, mitochondria with degenerative inner membranes. Collapse of mitochondria in axons was accompanied by focal disappearance of the cytoskeleton. Partial membrane loss at axon terminals was also evident, accompanied by degenerative membranes in the same areas. Imaging mass spectrometry showed a prominent increase of docosahexaenoic acidcontaining phosphatidylcholine in the gray matter, suggesting insufficient membrane remodeling in the presence of iPLA 2 ␤ deficiency. Prominent axonal degeneration in neuroaxonal dystrophy might be explained by the collapse of abnormal mitochondria after axonal transportation. Insufficient remodeling and degeneration of mitochondrial inner membranes and presynaptic membranes appear to be the cause of the neuroaxonal dystrophy in iPLA 2 ␤-KO mice.

Pantothenate Kinase-Associated Neurodegeneration

“…Insufficient remodeling and degeneration of mitochondrial inner membranes and presynaptic membranes has been shown in iPLA(2) knock-out (KO) mice [67] and mitochondrial structure and function are impaired in dPANK/fbl mutants [39].…”

Roles of Acidic Phospholipids and Nucleotides in Regulating Membrane Binding and Activity of a Calcium-independent Phospholipase A2 Isoform

“…GVIA-iPLA 2 additionally functions at mitochondria during apoptosis and has been implicated in rupturing the outer mitochondrial membrane to release cytochrome c into the cytoplasm (42,43). Mice harboring a deletion in iPLA2␤, the gene encoding GVIA-iPLA 2 , exhibit premature axonal degeneration, further indicating that the function of the enzyme is not limited to a unique subcellular site (21). These findings raise an important question.…”

“…iPLA2␤-deficient mice also accumulate axonal spheroids, which have been shown to contain numerous morphologically abnormal mitochondria (20). Additionally, significant axonal membrane degeneration was observed in mutant animals (21). Together, these data suggest that iPLA2␤ normally functions to maintain membrane architecture at multiple subcellular locations.…”

Diffuse Abnormality of Low to Moderately Organized White Matter in Schizophrenia

“…Our results further suggest the possibility that pathways, structures, or processes essential for axonal or dendritic integrity may be differentially affected in white matter tracts with FA in the 0.25 to 0.5 range and, hence, valuable targets for neurobiological exploration. For instance, the loss of function of the enzyme calciumindependent phospholipase A(2)b results in the failure of normal remodeling of membrane phospholipids and the disease infantile neuroaxonal dystrophy (Beck et al, 2011). Similarly, normal axonal structure and function requires the synthesis of glycosphingolipids by glucosylceramide synthase (Watanabe et al, 2010).…”