GDE2 is essential for neuronal survival in the postnatal mammalian spinal cord

Abstract

BackgroundGlycerophosphodiester phosphodiesterase 2 (GDE2) is a six-transmembrane protein that cleaves glycosylphosphatidylinositol (GPI) anchors to regulate GPI-anchored protein activity at the cell surface. In the developing spinal cord, GDE2 utilizes its enzymatic function to regulate the production of specific classes of motor neurons and interneurons; however, GDE2’s roles beyond embryonic neurogenesis have yet to be defined.MethodUsing a panel of histological, immunohistochemical, electrophysiological, behavioral, and biochemistry techniques, we characterized the postnatal Gde2 −/− mouse for evidence of degenerative neuropathology. A conditional deletion of Gde2 was used to study the temporal requirements for GDE2 in neuronal survival. Biochemical approaches identified deficits in the processing of GPI-anchored GDE2 substrates in the SOD1 G93A mouse model of familial Amyotrophic Lateral Sclerosis that shows robust motor neuron degeneration.ResultsHere we show that GDE2 expression continues postnatally, and adult mice lacking GDE2 exhibit a slow, progressive neuronal degeneration with pathologies similar to human neurodegenerative disease. Early phenotypes include vacuolization, microgliosis, cytoskeletal accumulation, and lipofuscin deposition followed by astrogliosis and cell death. Remaining motor neurons exhibit peripheral motor unit restructuring causing behavioral motor deficits. Genetic ablation of GDE2 after embryonic neurogenesis is complete still elicits degenerative pathology, signifying that GDE2’s requirement for neuronal survival is distinct from its involvement in neuronal differentiation. Unbiased screens identify impaired processing of Glypican 4 and 6 in Gde2 null animals, and Glypican release is markedly reduced in SOD1 G93A mice.ConclusionsThis study identifies a novel function for GDE2 in neuronal survival and implicates deregulated GPI-anchored protein activity in pathways mediating neurodegeneration. These findings provide new molecular insight for neuropathologies found in multiple disease settings, and raise the possibility of GDE2 hypofunctionality as a component of neurodegenerative disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0148-1) contains supplementary material, which is available to authorized users.

An Overview of the Role of Lipofuscin in Age-Related Neurodegeneration

“…On the other hand, chronic alcohol consumption induces increasing LF deposition in rat hippocampal neurons (Borges et al, 1986 ) and Purkinje (Lewandowska et al, 1994 ; Wenisch et al, 1997 ; Dlugos, 2015 ). Mice lacking the expression of glycerophosphodiester phosphodiesterase 2 (a six-transmembrane protein that cleaves glycosylphosphatidylinositol anchors) show early neurodegeneration with vacuolization, microgliosis, cytoskeletal accumulation, and LF deposition followed by astrogliosis and cell death (Cave et al, 2017 ).…”

Sequence-dependent trafficking and activity of GDE2, a GPI-specific phospholipase promoting neuronal differentiation

“…On a final note, GDE2 deficiency leads to progressive neurodegeneration in mice with motor neuron pathologies analogous to those in human disease, while it strongly correlates with poor clinical outcome in neuroblastoma (Cave et al, 2017;Matas-Rico et al, 2016). This raises the intriguing possibility that GDE2 dysfunction may underlie aspects of neurodegenerative disease and/or contribute to the pathophysiology of neuroblastoma.…”

“…Moreover, GDE2 expression strongly correlated with positive clinical outcome in neuroblastoma (Matas-Rico et al, 2016), an often lethal neurodevelopmental malignancy characterized by impaired differentiation (Ratner et al, 2016). Importantly, Gde2-knockout in mice leads to progressive neurodegeneration with pathologies reflecting human neurodegenerative disease, which was accompanied by reduced glypican release, implicating dysregulated GPI-anchored protein activity in neurodegeneration (Cave et al, 2017). Finally, GDE2 depletion in zebrafish embryos resulted in motility defects and impaired pancreas differentiation, as shown by reduced insulin expression, which was attributed in part to altered Notch regulation (van Veen et al, 2018).…”

Sequence-dependent trafficking of GDE2, a GPI-specific phospholipase promoting neuronal differentiation

“…Regarding pathophysiological implications, GDE2 deficiency predicts poor prognosis in neuroblastoma (Matas-Rico et al, 2016), while loss of GDE2 causes progressive neurodegeneration in mice with pathologies analogous to human disease (Cave et al, 2017).…”

“…Furthermore, GDE2 expression was found to strongly correlate with favorable outcome in neuroblastoma, a childhood malignancy characterized by impaired neuronal differentiation (Matas-Rico et al, 2016). In mice, Gde2 knockout led to progressive neurodegeneration in the spinal cord with pathologies reflecting human neurodegenerative disorders, which was accompanied by reduced glypican shedding (Cave et al, 2017). Finally, depletion of GDE2 in zebrafish embryos led to impaired motility and reduced pancreas differentiation and insulin expression; the latter phenotype could be rescued by human GDE2, indicating conservation of human and zebrafish GDE2 function (van Veen et al, 2018).…”