Infantile neuroaxonal dystrophy

Nardocci, Nardo; Zorzi, Giovanna; Farina, Laura; Binelli, S.; Scaioli, Widmer; Ciano, Claudia; Verga, Laura; Angelini, Lucia; Savoiardo, M.; Bugiani, Orso

doi:10.1212/wnl.52.7.1472

Cited by 112 publications

(80 citation statements)

References 16 publications

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“…There have been no reported descriptions of non-neurological symptoms, laboratory findings, or pathological changes in internal organs in INAD (Cowen and Olmstead, 1963;Nardocci et al, 1999), although dysfunction of spermatozoa (Bao et al, 2004), a reduced insulin secretory response (Zhao et al, 2010), and acceleration of age-related changes in bone morphology (Ramanadham et al, 2008) have been reported in adult iPLA 2 ␤-KO mice. The relatively mild phenotypes of iPLA 2 ␤ deficiency in nonneurological tissues suggest that iPLA 2 ␤ plays an especially important role in the nervous system, although it is widely distributed in various organs (Bao et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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

Beck¹,

Sugiura²,

et al. 2011

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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.

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Section: Discussionmentioning

confidence: 99%

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

Beck¹,

Sugiura²,

et al. 2011

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“…Moreover, although signs of hindlimb dysfunction were not detected in NTE-cKO mice until early adulthood (4 -5 months), in humans with recessively inherited NTE-deficiency spastic paraplegia begins in childhood (Rainier et al, 2008). Similarly, although calcium-independent phospholipase A2 (iPLA2)-deficient mice do not display hindlimb dysfunction and swollen spinal axons until one year of age (Shinzawa et al, 2008), humans with iPLA2-deficiency have neurological signs in infancy and die before puberty (Nardocci et al, 1999). Thus, in two mouse models of deficient phospholipid deacylation, neuropathological changes occur much more slowly than in the respective human syndrome.…”

Section: Discussionmentioning

confidence: 99%

Neuropathy Target Esterase Is Required for Adult Vertebrate Axon Maintenance

Read¹,

Li²,

Chao³

et al. 2009

J. Neurosci.

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The enzyme neuropathy target esterase (NTE) is present in neurons and deacylates the major membrane phospholipid, phosphatidylcholine (PtdCho). Mutation of the NTE gene or poisoning by neuropathic organophosphates-chemical inhibitors of NTE-causes distal degeneration of long spinal axons in humans. However, analogous neuropathological changes have not been reported in nestincre:NTEfl/fl mice with NTE-deficient neural tissue. Furthermore, altered PtdCho homeostasis has not been detected in NTE-deficient vertebrates. Here, we describe distal degeneration of the longest spinal axons in ϳ3-week-old nestin-cre:NTEfl/fl mice and in adult C57BL/6J mice after acute dosing with a neuropathic organophosphate: in both groups early degenerative lesions were followed by swellings comprising accumulated axoplasmic material. In mice dosed acutely with organophosphate, maximal numbers of lesions, in the longest spinal sensory axon tract, were attained within days and were preceded by a transient rise in neural PtdCho. In nestin-cre: NTEfl/fl mice, sustained elevation of PtdCho over many months was accompanied by progressive degeneration and massive swelling of axons in sensory and motor spinal tracts and by increasing hindlimb dysfunction. Axonal lesion distribution closely resembled that in hereditary spastic paraplegia (HSP). The importance of defective membrane trafficking in HSP and the association of NTE with the endoplasmic reticulum-the starting point for the constitutive secretory pathway and transport of neuronal materials into axonsprompted investigation for a role of NTE in secretion. Cultured NTE-deficient neurons displayed modestly impaired secretion, consistent with neuronal viability and damage in vivo initially restricted to distal parts of the longest axons.

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“…The pathological hallmark of the disease is the presence of large spheroids containing accumulated material primarily located in distal axons and nerve terminals. 5,6 These pathological changes are widely distributed throughout the brain and are also often found in peripheral nerves. A common feature of spheroids characterized by electron microscopy studies is the accumulation of membranes with tubulovesicular structures.…”

mentioning

confidence: 99%

Establishment of an Improved Mouse Model for Infantile Neuroaxonal Dystrophy That Shows Early Disease Onset and Bears a Point Mutation in Pla2g6

Wada

Yasuda

Miura³

et al. 2009

The American Journal of Pathology

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Calcium-independent group VIA phospholipase A 2 (iPLA 2 ␤), encoded by PLA2G6, has been shown to be involved in various physiological and pathological processes, including immunity, cell death, and cell membrane homeostasis. Mutations in the PLA2G6 gene have been recently identified in patients with infantile neuroaxonal dystrophy (INAD). Subsequently, it was reported that similar neurological impairment occurs in gene-targeted mice with a null mutation of iPLA 2 ␤, whose disease onset became apparent approximately 1 to 2 years after birth. Here, we report the establishment of an improved mouse model for INAD that bears a point mutation in the ankyrin repeat domain of Pla2g6 generated by N-ethyl-N-nitrosourea mutagenesis. These mutant mice developed severe motor dysfunction, including abnormal gait and poor performance in the hanging grip test, as early as 7 to 8 weeks of age, in a manner following Mendelian law. Neuropathological examination revealed widespread formation of spheroids containing tubulovesicular membranes similar to human INAD. Molecular and biochemical analysis revealed that the mutant mice expressed Pla2g6 mRNA and protein , but the mutated Pla2g6 protein had no glycerophospholipid-catalyzing enzyme activity. Because of the significantly early onset of the disease , this mouse mutant (Pla2g6-inad) could be highly useful for further studies of pathogenesis and experimental interventions in INAD and neurodegeneration.

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Infantile neuroaxonal dystrophy

Abstract: EMG and MRI abnormalities are the earliest and most suggestive signs of INAD, which has a clinical and radiologic spectrum that is broader than reported previously.

Cited by 112 publications

References 16 publications

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

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

Neuropathy Target Esterase Is Required for Adult Vertebrate Axon Maintenance

Establishment of an Improved Mouse Model for Infantile Neuroaxonal Dystrophy That Shows Early Disease Onset and Bears a Point Mutation in Pla2g6

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Infantile neuroaxonal dystrophy

Abstract: EMG and MRI abnormalities are the earliest and most suggestive signs of INAD, which has a clinical and radiologic spectrum that is broader than reported previously.

Cited by 112 publications

References 16 publications

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

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

Neuropathy Target Esterase Is Required for Adult Vertebrate Axon Maintenance

Establishment of an Improved Mouse Model for Infantile Neuroaxonal Dystrophy That Shows Early Disease Onset and Bears a Point Mutation in Pla2g6

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

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