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Dysregulation of the (immuno)proteasome pathway in malformations of cortical development.

Abstract：

BACKGROUND:The proteasome is a multisubunit enzyme complex involved in protein degradation, which is essential for many cellular processes. During inflammation, the constitutive subunits are replaced by their inducible counterparts, resulting in the formation of the immunoproteasome. METHODS:We investigated the expression pattern of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits using immunohistochemistry in malformations of cortical development (MCD; focal cortical dysplasia (FCD) IIa and b, cortical tubers from patients with tuberous sclerosis complex (TSC), and mild MCD (mMCD)). Glial cells in culture were used to elucidate the mechanisms regulating immunoproteasome subunit expression. RESULTS:Increased expression was observed in both FCD II and TSC; β1, β1i, β5, and β5i were detected (within cytosol and nucleus) in dysmorphic neurons, balloon/giant cells, and reactive astrocytes. Glial and neuronal nuclear expression positively correlated with seizure frequency. Positive correlation was also observed between the glial expression of constitutive and immunoproteasome subunits and IL-1β. Accordingly, the proteasome subunit expression was modulated by IL-1β in human astrocytes in vitro. Expression of both constitutive and immunoproteasome subunits in FCD II-derived astroglial cultures was negatively regulated by treatment with the immunomodulatory drug rapamycin (inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is activated in both TSC and FCD II). CONCLUSIONS:These observations support the dysregulation of the proteasome system in both FCD and TSC and provide new insights on the mechanism of regulation the (immuno)proteasome in astrocytes and the molecular links between inflammation, mTOR activation, and epilepsy.

journal_name

J Neuroinflammation

journal_title

Journal of neuroinflammation

authors

van Scheppingen J,Broekaart DW,Scholl T,Zuidberg MR,Anink JJ,Spliet WG,van Rijen PC,Czech T,Hainfellner JA,Feucht M,Mühlebner A,van Vliet EA,Aronica E

doi

10.1186/s12974-016-0662-z

subject

Has Abstract

pub_date

2016-08-26 00:00:00

pages

202

issue

1

issn

1742-2094

pii

10.1186/s12974-016-0662-z

journal_volume

13

pub_type

杂志文章

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