Contribution of Cystatin C Gene Polymorphisms to Cerebral White Matter Lesions

Mitaki, Shingo; Nagai, Atsushi; Sheikh, Abdullah Md.; Terashima, Masaharu; Isomura, Minoru; Nabika, Toru; Yamaguchi, Shûhei

doi:10.1159/000331921

Cited by 8 publications

(14 citation statements)

References 56 publications

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“…Thus, this is the first study to confirm the functional effect of rs3118869 on transcription and we also demonstrated a novel association with CTSL protein level. There are no previous studies of the CST3 rs6036478 polymorphism in the literature, but this SNP is part of a haplotype of SNPs in high linkage disequilibrium (all r 2 .0.92), which has been shown to influence serum/plasma CST3 levels [22][23][24][25]. Our observation that the A (minor) allele of rs6036478 was associated with lower basal CST3 mRNA (online supplementary table S6) is consistent with these previous data and is novel in the context of COPD.…”

Section: Discussionmentioning

confidence: 99%

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema

et al. 2013

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Alveolar macrophages play an important role in chronic obstructive pulmonary disease via production of matrix metalloproteinases (MMPs) and cathepsins as well as their inhibitors, tissue inhibitors of metalloproteinases and cystatin C. We hypothesised that expression levels of these molecules by alveolar macrophages at baseline and after stimulation would be influenced by genotype and associated with chronic obstructive pulmonary disease phenotypes.Quantitative PCR and ELISAs/gelatine zymography were used to investigate expression levels of mRNA and protein, respectively. The relationships of expression with genotype, pulmonary function and emphysema were analysed.The results showed that basal expression level of MMP12 mRNA was inversely related to the diffusing capacity of the lung for carbon monoxide/alveolar volume and to forced expiratory volume in 1 s/forced vital capacity after correction for multiple comparisons. The expression level of MMP12 protein stimulated with lipopolysaccharide was also inversely related to the diffusing capacity of the lung for carbon monoxide/ alveolar volume and was positively related to the extent of emphysema. The basal expression of MMP1 mRNA was positively correlated with the extent of emphysema. Cathepsin L protein level was positively associated with forced expiratory volume in 1 s % predicted.We conclude that increased MMP12 and MMP1 expression may play a role in the pathogenesis of emphysema. Cathepsin L and MMP9 may be involved in the development of airflow limitation. @ERSpublications MMP12 expression may play a role in the pathogenesis of emphysema and airflow limitation

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Section: Discussionmentioning

confidence: 99%

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema

et al. 2013

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“…For updated information on the linkage of the CST3 polymorphism with AD, see the Alzgene Internet site of the Alzheimer Research Forum. In addition to AD, polymorphisms in the CysC gene have been associated with the likelihood of developing two additional neurodegenerative disorders: frontotemporal lobar degeneration (Benussi et al, 2010) and cerebral white matter lesions (Mitaki et al, 2011). …”

Section: Cysc In Alzheimer’s Diseasementioning

confidence: 99%

Cystatin C in aging and in Alzheimer’s disease

Mathews

Levy

2016

Ageing Research Reviews

101

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Under normal conditions, the function of catalytically active proteases is regulated, in part, by their endogenous inhibitors, and any change in the synthesis and/or function of a protease or its endogenous inhibitors may result in inappropriate protease activity. Altered proteolysis as a result of an imbalance between active proteases and their endogenous inhibitors can occur during normal aging, and such changes have also been associated with multiple neuronal diseases, including Amyotrophic Lateral Sclerosis (ALS), rare heritable neurodegenerative disorders, ischemia, some forms of epilepsy, and Alzheimer’s disease (AD). One of the most extensively studied endogenous inhibitor is the cysteine-protease inhibitor cystatin C (CysC). Changes in the expression and secretion of CysC in the brain have been described in various neurological disorders and in animal models of neurodegeneration, underscoring a role for CysC in these conditions. In the brain, multiple in vitro and in vivo findings have demonstrated that CysC plays protective roles via pathways that depend upon the inhibition of endosomal-lysosomal pathway cysteine proteases, such as cathepsin B (Cat B), via the induction of cellular autophagy, via the induction of cell proliferation, or via the inhibition of amyloid-β (Aβ) aggregation. We review the data demonstrating the protective roles of CysC under conditions of neuronal challenge and the protective pathways induced by CysC under various conditions. Beyond highlighting the essential role that balanced proteolytic activity plays in supporting normal brain aging, these findings suggest that CysC is a therapeutic candidate that can potentially prevent brain damage and neurodegeneration.

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“…Our analysis demonstrated that the polymorphism at these three positions was the haplotype of CST3 gene that affected the plasma concentration and brain white matter lesions. Several studies have demonstrated that the polymorphism in CST3 gene can affect its production and secretion from the cells, and its concentration in serum and cerebrospinal fluid [23][24][25][26][27] . Interestingly, a study found that the minor allele carriers at −82, −78, −5 and +148 positions had lower plasma CST3 concentration 19 .…”

Section: Discussionmentioning

confidence: 99%

“…Since CSF profile broadly represents the pathophysiology of CNS, useful information might be obtained by investigating the effects of gene polymorphism on CSF CST3 concentration in relation to CNS small vessel diseases. Our previous case-control study demonstrated that the haplotype of 3 SNPs in CST3 gene (−82C/+4C/+148A) is related to lower plasma CST3 concentration and risk of severe cerebral white matter lesion 24 . Since the study was done in a small and targeted population, a large-scale study is warranted to further clarify the association of CST3 polymorphism with white matter disease occurrence and cognitive function in general population.…”

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confidence: 97%

Association between cystatin C gene polymorphism and the prevalence of white matter lesion in elderly healthy subjects

Maniwa

Yano

Sheikh

et al. 2020

Sci Rep

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Cystatin C (CST3) is a cysteine protease inhibitor abundant in the central nervous system, and demonstrated to have roles in several pathophysiological processes including vascular remodeling and inflammation. Previously, we showed a relation of CST3 gene polymorphisms with deep and subcortical white matter hyperintensity (DSWMH) in a small case-control study. In this study, we aimed to investigate the relation in a larger cross-sectional study. Participants of a brain health examination program were recruited (n = 1795) in the study, who underwent routine blood tests and cognitive function tests. Cerebral white matter changes were analyzed by MRI. Additionally, 7 single nucleotide polymorphisms (SNPs) (−82G/C, −78T/G, −5G/A, +4A/C, +87C/T, +148G/A and +213G/A) in the promoter and coding regions of CST3 gene were examined. Among them, carriers of the minor allele haplotype −82C/+4C/+148A were significantly associated with decreased CST3 concentration in the plasma. Unadjusted analysis did not show significant relation between carriers of the minor allele haplotype and periventricular hyperintensity (PVH), but DSWMH was marginally (p < 0.054) increased in this group. After adjusting the effects of other variables like age and kidney function, logistic regression analysis revealed that carriers of the minor allele haplotype were at a significantly increased risk of developing both pVH and DSWMH. thus, our results suggest that carriers of the minor allele haplotype −82C/+4C/+148A of CST3 gene could be at an increased risk to develop cerebral white matter disturbance.

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Contribution of Cystatin C Gene Polymorphisms to Cerebral White Matter Lesions

Cited by 8 publications

References 56 publications

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema

Alveolar macrophage proteinase/antiproteinase expression in lung function and emphysema

Cystatin C in aging and in Alzheimer’s disease

Association between cystatin C gene polymorphism and the prevalence of white matter lesion in elderly healthy subjects

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