Inhibition of the de-myelinating properties of Aicardi-Goutières Syndrome lymphocytes by cathepsin D silencing

Pulliero, Alessandra; Marengo, Barbara; Longobardi, M.; Fazzi, Elisa; Orcesi, Simona; Olivieri, Ivana; Cereda, Cristina; Domenicotti, Cinzia; Balottin, Umberto; Izzotti, Alberto

doi:10.1016/j.bbrc.2012.11.131

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…19 The myelin pathology has been related to overexpression of cathepsin-D in CSF lymphocytes, a pro-apoptotic factor with myelin-directed protease activity induced by IFN- α . 20 CSF of our patient was not available to verify IFN- α and cathepsin-D levels, but astrocytic IFN- α expression and apoptotic loss of oligodendrocytes were conspicuous in the white matter, whereas influx of lymphocytes was negligible. This points to mechanisms other than lymphocytic neurotoxicity in maintaining oligodendrocytic pathology in AGS, at least in older patients in whom CSF lymphocyte numbers have fallen to normal.…”

Section: Discussionmentioning

confidence: 92%

Interferon‐α and the calcifying microangiopathy in Aicardi–Goutières syndrome

Klok

Bakels

Postma

et al. 2015

Ann Clin Transl Neurol

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Aicardi–Goutières syndrome is a leukoencephalopathy with calcifications and increased cerebrospinal fluid interferon-α. The relation between interferon-α and brain pathology is poorly understood. We report a patient with mutations in the disease-associated gene SAMHD1. Neuropathology showed an extensive microangiopathy with calcifications consistently associate with blood vessels. In an in vitro model of the microangiopathy, interferon-α enhanced vascular smooth muscle cell-derived calcifications. The noninfarcted white matter harbored apoptotic oligodendrocytes and increased numbers of oligodendrocyte progenitors. These findings better define the white matter pathology and provide evidence that interferon-α plays a direct pathogenetic role in the calcifying angiopathy typical of this disease.

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Section: Discussionmentioning

confidence: 92%

Interferon‐α and the calcifying microangiopathy in Aicardi–Goutières syndrome

Klok

Bakels

Postma

et al. 2015

Ann Clin Transl Neurol

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“…Substantial support for IFN-α playing a pathogenic role in premature atherosclerosis in lupus has been provided by several groups, with IFN-α inhibiting production or survival of endothelial progenitor cells that are important for vascular repair and promoting foam cell formation (113, 114). A contribution of IFN-α to the central nervous system manifestations of lupus is suggested by the recent observation that neurotoxic lymphocytes can be activated by IFN-α and mediate CNS damage based on their toxic effects on astrocytes (115). …”

Section: Contribution Of Ifn-i To Immunopathogenesis Of Slementioning

confidence: 99%

Type I Interferon in the Pathogenesis of Lupus

Crow

2014

The Journal of Immunology

443

376

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Investigations of patients with systemic lupus erythematosus (SLE) have applied insights from studies of the innate immune response to define type I interferon (IFN-I), with IFN-α the dominant mediator, as central to the pathogenesis of this prototype systemic autoimmune disease. Genetic association data identify regulators of nucleic acid degradation and components of TLR-independent, endosomal TLR-dependent, and IFN-I signaling pathways as contributors to lupus disease susceptibility. Together with a gene expression signature characterized by IFNI-induced gene transcripts in lupus blood and tissue, those data support the conclusion that many of the immunologic and pathologic features of this disease are a consequence of a persistent self-directed immune reaction driven by IFN-I and mimicking a sustained anti-virus response. This expanding knowledge of the role of IFN-I and the innate immune response suggests candidate therapeutic targets that are being tested in lupus patients.

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“…Histological studies have shown infiltrating T cells (CD3+ cells) in the brains of AGS individuals , which accompanied by CSF lymphocytosis in AGS could activate astrocytes. One study has directly addressed this lymphocyte–astrocyte cross talk and reported that lymphocytes can cause astrogliosis through activation of the pro‐apoptotic enzyme cathepsin D, which upon blocking is protective and decreases astrocyte activation .…”

Section: Impact Of Peripheral Inflammation On Astrocytesmentioning

confidence: 99%

Astrocytes, an active player in Aicardi–Goutières syndrome

et al. 2018

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Aicardi-Goutières syndrome (AGS) is an early-onset, autoimmune and genetically heterogeneous disorder with severe neurologic injury. Molecular studies have established that autosomal recessive mutations in one of the following genes are causative: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1/MDA5. The phenotypic presentation and pathophysiology of AGS is associated with over-production of the cytokine Interferon-alpha (IFN-α) and its downstream signaling, characterized as type I interferonopathy. Astrocytes are one of the major source of IFN in the central nervous system (CNS) and it is proposed that they could be key players in AGS pathology. Astrocytes are the most ubiquitous glial cell in the CNS and perform a number of crucial and complex functions ranging from formation of blood-brain barrier, maintaining ionic homeostasis, metabolic support to synapse formation and elimination in healthy CNS. Involvement of astrocytic dysfunction in neurological diseases-Alexander's disease, Epilepsy, Alzheimer's and amyotrophic lateral sclerosis (ALS)-has been well-established. It is now known that compromised astrocytic function can contribute to CNS abnormalities and severe neurodegeneration, nevertheless, its contribution in AGS is unclear. The current review discusses known molecular and cellular pathways for AGS mutations and how it stimulates IFN-α signaling. We shed light on how astrocytes might be key players in the phenotypic presentations of AGS and emphasize the cell-autonomous and non-cell-autonomous role of astrocytes. Understanding the contribution of astrocytes will help reveal mechanisms underlying interferonopathy and develop targeted astrocyte specific therapeutic treatments in AGS.

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Inhibition of the de-myelinating properties of Aicardi-Goutières Syndrome lymphocytes by cathepsin D silencing

Cited by 7 publications

References 26 publications

Interferon‐α and the calcifying microangiopathy in Aicardi–Goutières syndrome

Interferon‐α and the calcifying microangiopathy in Aicardi–Goutières syndrome

Type I Interferon in the Pathogenesis of Lupus

Astrocytes, an active player in Aicardi–Goutières syndrome

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