Abstract
Stefin B (cystatin B) is an inhibitor of endo-lysosomal cysteine cathepsin, and the loss-of-function mutations in the stefin B gene were reported in patients with Unverricht–Lundborg disease (EPM1), a form of progressive myoclonus epilepsy. Stefin B-deficient mice, a mouse model of the disease, display key features of EPM1, including myoclonic seizures. Although the underlying mechanism is not yet completely clear, it was reported that the impaired redox homeostasis and inflammation in the brain contribute to the progression of the disease. In the present study, we investigated if lipopolysaccharide (LPS)-triggered neuroinflammation affected the protein levels of redox-sensitive proteins: thioredoxin (Trx1), thioredoxin reductase (TrxR), peroxiredoxins (Prxs) in brain and cerebella of stefin B-deficient mice. LPS challenge was found to result in a marked elevation of Trx1 and TrxR in the brain and cerebella of stefin B deficient mice, while Prx1 was upregulated only in cerebella after LPS challenge. Mitochondrial peroxiredoxin 3 (Prx3), was upregulated also in the cerebellar tissue lysates prepared from unchallenged stefin B deficient mice, while after LPS challenge Prx3 was upregulated in stefin B deficient brain and cerebella. Our results imply the role of oxidative stress in the progression of the disease.
Highlights
Unverricht–Lundbordg disease (EPM1, OMIM 254800) is a type of progressive myoclonus epilepsy, which is inherited autosomal recessively
The most frequent mutation is an expansion of a dodecamere repeat in the 50 untranslated region of the stefin B gene, which results in lower expression of stefin B protein, while frameshift mutations and deletions are less common in EPM1 patients [4]
Tiroxiredoxin (Trx) and thioredoxin reductase (TrxR) Are Upregulated in LPS Induced Neuroinflamamtion in Brain stimulated stefin B-deficient macrophages and spleens
Summary
Unverricht–Lundbordg disease (EPM1, OMIM 254800) is a type of progressive myoclonus epilepsy, which is inherited autosomal recessively. The underlying cause is mutations in the gene encoding stefin B (cystatin B), an intracellular endogenous inhibitor of cysteine cathepsins [2,3]. Stefin B is found in cytosol, as well as in the nucleus and mitochondria [7,8,9,10]. We reported that stefin B interacted with nucleosomes, with histones H2A.Z, H2B, and H3 and cathepsin L in the nucleus [8]. A recent study confirmed that stefin B acts as an endogenous modulator of histone H3 tail trimming by the inhibition of cathepsins B and L in the nuclei of mouse neural progenitor cells [11]. It was demonstrated that stefin B expression is higher upon oxidative
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