PAI-1 production by reactive astrocytes drives tissue dysfibrinolysis in multiple sclerosis models

Lebas, Héloïse; Guérit, Sylvaine; Picot, Audrey; Boulay, Anne; Fournier, Antoine; Vivien, Denis; Salmon, Martine Cohen; Docagne, Fabián; Bardou, Isabelle

doi:10.1007/s00018-022-04340-z

Cited by 6 publications

(3 citation statements)

References 43 publications

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“…SERPINE1 may play a role in neurodegeneration/neuroprotection via extracellular matrix remodelling, excitotoxicity, blood-brain barrier opening, and recruitment and activation of microglia [30], while secretion of SERPINE2 by astroglia/oligodendroglia at the axoglial junction is believed to regulate nodal length and myelin structure in the optic nerve and corpus callosum [13]. Aberrant expression of SERPINE1 has been linked to neurodegenerative diseases, including Alzheimer’s [1, 27], Parkinson’s disease [57], and MS [28]. Serpinopathies, e.g., ALS (with SERPINE2 accumulation), are characterized by neuronal inclusion bodies that accumulate within the ER and elicit an ER overload response and cell death signalling, [10, 30, 43, 52].…”

Section: Discussionmentioning

confidence: 99%

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

Ahuja,

Vandenabeele,

Nami

et al. 2024

Preprint

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Wolfram syndrome (WS) is a rare childhood disease characterized by diabetes mellitus, diabetes insipidus, blindness, deafness, neurodegeneration and eventually early death, due to autosomal recessive mutations in theWFS1(andWFS2) gene. While it is categorized as a neurodegenerative disease, it is increasingly becoming clear that other cell types besides neurons may be affected and contribute to the pathogenesis. MRI studies in patients and phenotyping studies in WS rodent models indicate white matter/myelin loss, implicating a role for oligodendroglia in WS-associated neurodegeneration. In this study, we sought to determine if oligodendroglia are affected in WS and whether their dysfunction may be the primary cause of the observed optic neuropathy and brain neurodegeneration. We demonstrate that 7.5-month-oldWfs1Δexon8mice display signs of abnormal myelination and a reduced number of oligodendrocyte precursor cells (OPCs) as well as abnormal axonal conduction in the optic nerve. An MRI study of the brain furthermore revealed grey and white matter loss in the cerebellum, brainstem, and superior colliculus, as is seen in WS patients. To further dissect the role of oligodendroglia in WS, we performed a transcriptomics study of WS patient iPSC-derived OPCs and pre-myelinating oligodendrocytes. Transcriptional changes compared to isogenic control cells were found for genes with a role in ER function. However, a deep phenotyping study of these WS patient iPSC-derived oligodendroglia unveiled normal differentiation, mitochondria-associated endoplasmic reticulum (ER) membrane interactions and mitochondrial function, and no overt signs of ER stress. Overall, the current study indicates that oligodendroglia functions are largely preserved in the WS mouse and patient iPSC-derived models used in this study. These findings do not support a major defect in oligodendroglia function as the primary cause of WS, and warrant further investigation of neurons and neuron-oligodendroglia interactions as a target for future neuroprotective or -restorative treatments for WS.

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Section: Discussionmentioning

confidence: 99%

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

Ahuja,

Vandenabeele,

Nami

et al. 2024

Preprint

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“…Experimental models show the importance of PAI-1 (overexpressed by reactive astrocytes leading dysfibrinolysis in MS). (Lebas H, et al [3]) Further studies should be performed to evaluate the role of PAI mutation in MS patients and also for vascular diseases. The thrombotic risk factors associated with MS such as obesity, smoking, endothelial dysfunction, platelet activation, thrombophilia are pro-thrombotic conditions.…”

Section: Discussionmentioning

confidence: 99%

"Thrombus in the Brachiocephalic Trunk in Patient with Bovine Aortic Arch Variation Mimics a Stroke or Multiple Sclerosis"

Cholakova

2023

BJSTR

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Embolism is mostly associated with arterial rather than venous injury, and with neuronal infarction rather than waste of myelin. Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) with difficult differential diagnosis. MS and stroke have general risk factors. The immune mechanisms of stroke are similar to neurodegenerative diseases and are adjunct to neuroinflammation. In autoimmune diseases the inflammation could increase risk for stroke or amplify the effect of conventional stroke risk factors. In the present case, the young patient was with clinical features susceptible for demyelinating disease. After performed MRI, cerebrospinal fluid examination, evoked potentials and screening for thrombophilia, multiple sclerosis was excluded. Ultrasound doppler examination and computed tomography (CT) angiography was performed because of the acute complaints of numbness and pain in right hand. It was found complete occlusion of the proximal half of the right ulnar artery, occlusion of the distal part of radial artery with its branches forming the superficial and deep palmar arches. The patient was diagnosed with parenchymal thrombus in brachiocephalic trunk, involving more than 80% of its lumen. When there is clinical presentation of relapses with neurological symptoms typical for MS in the differential diagnoses a vascular embolization should be considered and screening for thrombophilia could be useful. Multiple sclerosis could have difficult differential diagnose and a couple of new trials and experimental models show the significance of PAI-1 in etiology of neuroinflammation and neurodegeneration in multiple sclerosis, as well as a risk factor for thrombotic events in young adults.

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“…Fibrin(ogen) deposits, usually degraded by the PAS, lead an autoimmune response and following demyelination. However, the PAS disruption is not well understood in this disorder [9,10]. Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) because of genetic and environmental factors.…”

Section: Introductionmentioning

confidence: 99%

"PAI mutation 4G/5G- Coagulopathy Risk Factor for Stroke or Multiple Sclerosis"

2024

BJSTR

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Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) with difficult differential diagnosis. The new trials show the importance of PAI-1 in etiology of neuroinflammation and neurodegeneration in multiple sclerosis. PAI mutation of 4G/5G is a risk factor for thrombotic events in young adults. We present a prospective study with patient diagnosed with MS and examined for thrombophilia, especially PAI mutation 4G/5G. Observational study was performed to evaluate the incidence of PAI mutation in patients with ischemic stroke and healthy control group. A comparison analyses was done in the three groups of patients. PAI mutation could play a role as a risk factor for neuroinflammation in MS.

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PAI-1 production by reactive astrocytes drives tissue dysfibrinolysis in multiple sclerosis models

Cited by 6 publications

References 43 publications

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

A deep phenotyping study in mouse and iPSC models to understand the role of oligodendroglia in optic neuropathy in Wolfram syndrome

"Thrombus in the Brachiocephalic Trunk in Patient with Bovine Aortic Arch Variation Mimics a Stroke or Multiple Sclerosis"

"PAI mutation 4G/5G- Coagulopathy Risk Factor for Stroke or Multiple Sclerosis"

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