A role for the urokinase-type plasminogen activator system in amyotrophic lateral sclerosis

Glas, Martin; Popp, Bernadette; Angele, B.; Koedel, Uwe; Chahli, C.; Schmalix, Wolfgang A.; Anneser, Johanna; Pfister, Hans‐Walter; Lorenzl, Stefan

doi:10.1016/j.expneurol.2007.07.007

Cited by 26 publications

(13 citation statements)

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“…We found that none of the evaluated ALS samples showed affinity towards proteins present at synaptic terminals, such as synaptotagmin I, syntaxin 1A, synaptophysin and synaptobrevin II, all of which were readily detectable in the original lysates (Figure S3f). Other candidates to test in the future include extracellular matrix molecules, neurotrophins receptors and proteins involved in synaptogenesis and axon guidance, due to their proposed role during neurodegeneration (Dawbarn and Allen 2003; Glas et al. 2007; Schmidt et al.…”

Section: Discussionmentioning

confidence: 99%

Amyotrophic lateral sclerosis‐immunoglobulins selectively interact with neuromuscular junctions expressing P/Q‐type calcium channels

González

Kotler

Vattino

et al. 2011

Journal of Neurochemistry

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive neuromuscular dysfunction and decrease in the number of upper and lower motoneurons (Mulder 1982). Clinical manifestations include fatigue, fasciculations, spasticity, hyperreflexia, weakness and muscle atrophy, ultimately leading to paralysis and death (Rowland 1998 Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a gradual loss of motoneurons. The majority of ALS cases are associated with a sporadic form whose etiology is unknown. Several pieces of evidence favor autoimmunity as a potential contributor to sporadic ALS pathology. To gain understanding concerning possible antigens interacting with IgGs from sporadic ALS patients (ALSIgGs), we studied immunoreactivity against neuromuscular junction (NMJ), spinal cord and cerebellum of mice with and without the Ca V 2.1 pore-forming subunit of the P/Q-type voltage-gated calcium (Ca 2+ ) channel. ALS-IgGs showed a strong reactivity against NMJs of wild-type diaphragms. ALSIgGs also increased muscle miniature end-plate potential frequency, suggesting a functional role for ALS-IgGs on synaptic signaling. In support, in mice lacking the Ca V 2.1 subunit ALS-IgGs showed significantly reduced NMJ immunoreactivity and did not alter spontaneous acetylcholine release. This difference in reactivity was absent when comparing N-type Ca 2+ channel wild-type or null mice. These results are particularly relevant because motoneurons are known to be early pathogenic targets in ALS. Our findings add further evidence supporting autoimmunity as one of the possible mechanisms contributing to ALS pathology. They also suggest that serum autoantibodies in a subset of ALS patients would interact with NMJ proteins down-regulated when P/Qtype channels are absent.

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Section: Discussionmentioning

confidence: 99%

Amyotrophic lateral sclerosis‐immunoglobulins selectively interact with neuromuscular junctions expressing P/Q‐type calcium channels

González

Kotler

Vattino

et al. 2011

Journal of Neurochemistry

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“…Background densities for each lane were then subtracted from enzymatic values obtained from density measurements of each band. This method has been used routinely for the detection of uPA activity in diseased brain (Burk et al, 2008) and spinal cord (Glas et al, 2007). …”

Section: Methodsmentioning

confidence: 99%

Transcriptional Activation of Endothelial Cells by TGFβ Coincides with Acute Microvascular Plasticity following Focal Spinal Cord Ischaemia/Reperfusion Injury

et al. 2009

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Microvascular dysfunction, loss of vascular support, ischaemia and sub-acute vascular instability in surviving blood vessels contribute to secondary injury following SCI (spinal cord injury). Neither the precise temporal profile of the cellular dynamics of spinal microvasculature nor the potential molecular effectors regulating this plasticity are well understood. TGFβ (transforming growth factor β) isoforms have been shown to be rapidly increased in response to SCI and CNS (central nervous system) ischaemia, but no data exist regarding their contribution to microvascular dysfunction following SCI. To examine these issues, in the present study we used a model of focal spinal cord ischaemia/reperfusion SCI to examine the cellular response(s) of affected microvessels from 30 min to 14 days post-ischaemia. Spinal endothelial cells were isolated from affected tissue and subjected to focused microarray analysis of TGFβ-responsive/related mRNAs 6 and 24 h post-SCI. Immunohistochemical analyses of histopathology show neuronal disruption/loss and astroglial regression from spinal microvessels by 3 h post-ischaemia, with complete dissolution of functional endfeet (loss of aquaporin-4) by 12 h post-ischaemia. Coincident with this microvascular plasticity, results from microarray analyses show 9 out of 22 TGFβ-responsive mRNAs significantly up-regulated by 6 h post-ischaemia. Of these, serpine 1/PAI-1 (plasminogen-activator inhibitor 1) demonstrated the greatest increase (>40-fold). Furthermore, uPA (urokinase-type plasminogen activator), another member of the PAS (plasminogen activator system), was also significantly increased (>7.5-fold). These results, along with other select up-regulated mRNAs, were confirmed biochemically or immunohistochemically. Taken together, these results implicate TGFβ as a potential molecular effector of the anatomical and functional plasticity of microvessels following SCI.

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“…Expression of GPI-anchored CD59 has been shown to be neuroprotective in neurons and decreased expression has been reported in the brains of patients with Alzheimer’s Disease (AD) [15], and aberrant Glypican processing has been detected in the context of AD and Niemann-Pick Disease [16, 17]. In Amyotrophic Lateral Sclerosis (ALS), expression of GPI-anchored Ephrin A5 and uPAR are both significantly altered [18, 19]. These observations underscore the importance of GPI-anchor regulation in disease, and open an avenue for GDE2 dysfunction to mediate aspects of neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

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

Cave¹,

Park²,

Rodriguez³

et al. 2017

Mol Neurodegeneration

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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.

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A role for the urokinase-type plasminogen activator system in amyotrophic lateral sclerosis

Cited by 26 publications

References 40 publications

Amyotrophic lateral sclerosis‐immunoglobulins selectively interact with neuromuscular junctions expressing P/Q‐type calcium channels

Amyotrophic lateral sclerosis‐immunoglobulins selectively interact with neuromuscular junctions expressing P/Q‐type calcium channels

Transcriptional Activation of Endothelial Cells by TGFβ Coincides with Acute Microvascular Plasticity following Focal Spinal Cord Ischaemia/Reperfusion Injury

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

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