Measurement of cystatin C functional activity in the cerebrospinal fluid of amyotrophic lateral sclerosis and control subjects

Wilson, Meghan; Boumaza, Imene; Bowser, Robert

doi:10.1186/2045-8118-10-15

Cited by 31 publications

(26 citation statements)

References 29 publications

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“…Haptoglobin is an acute phase protein 96-98 and cystatin C is a proteinase inhibitor abundant in CSF. 99-101 In this study, these proteins were only upregulated in corticosteroid-treated CSM-affected dogs, which is consistent with a corticosteroid-related increased as described in other studies. 102-104 Transthyretin is a neuroprotective negative acute phase protein and it is often downregulated in human neurological diseases.…”

Section: Discussionsupporting

confidence: 92%

Proteomic Analysis of Cerebrospinal Fluid in Canine Cervical Spondylomyelopathy

Martín-Vaquero

Costa

Allen

et al. 2015

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Study Design Prospective study. Objective To identify proteins with differential expression in the cerebrospinal fluid (CSF) from 15 clinically normal (control) dogs and 15 dogs with cervical spondylomyelopathy (CSM). Summary of Background Data Canine CSM is a spontaneous, chronic, compressive cervical myelopathy similar to human cervical spondylotic myelopathy. There is a limited knowledge of the molecular mechanisms underlying these conditions. Differentially expressed CSF proteins may contribute with novel information about the disease pathogenesis in both dogs and humans. Methods Protein separation was performed with two-dimensional electrophoresis. A Student’s t-test was used to detect significant differences between groups (P < 0.05). Three comparisons were made: 1) control versus CSM-affected dogs, 2) control versus non-corticosteroid treated CSM-affected dogs, and 3) non-corticosteroid treated CSM-affected versus corticosteroid treated CSM-affected dogs. Protein spots exhibiting at least a statistically significant 1.25-fold change between groups were selected for subsequent identification with capillary-liquid chromatography tandem mass spectrometry. Results A total of 96 spots had a significant average change of at least 1.25-fold in one of the three comparisons. Compared to the CSF of control dogs, CSM-affected dogs demonstrated increased CSF expression of eight proteins including vitamin D-binding protein, gelsolin, creatine kinase B-type, angiotensinogen, alpha-2-HS-glycoprotein, SPARC, calsyntenin-1, and complement C3, and decreased expression of pigment epithelium-derived factor, prostaglandin-H2 D-isomerase, apolipoprotein E, and clusterin. In the CSF of CSM-affected dogs, corticosteroid treatment increased the expression of haptoglobin, transthyretin isoform 2, cystatin C-like, apolipoprotein E, and clusterin, and decreased the expression of angiotensinogen, alpha-2-HS-glycoprotein, and gelsolin. Conclusions Many of the differentially expressed proteins are associated with damaged neural tissue, bone turnover, and/or compromised blood-spinal cord barrier. The knowledge of the protein changes that occur in CSM and upon corticosteroid treatment of CSM-affected patients will aid in further understanding the pathomechanisms underlying this disease.

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Section: Discussionsupporting

confidence: 92%

Proteomic Analysis of Cerebrospinal Fluid in Canine Cervical Spondylomyelopathy

Martín-Vaquero

Costa

Allen

et al. 2015

Spine

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“…We previously reported that NEP cleaved the Tyr 4 -Ile 5 bond of ANG-(1-7) in the BBM fraction from rat kidney (3); however, NEP is a metallopeptidase that is insensitive to thiol inhibitors such as PCMB, and the specific NEP inhibitor SCH39370 did not attenuate the metabolism of ANG-(1-7) (data not shown). Other thiol-sensitive peptidases localized in CSF include cystatin C, cathepsins, and papain, but their participation in the hydrolysis of ANG-(1-7) to ANG-(1-4) has not been described in CSF (45,63,80). Moreover, we have not established whether the thiol-sensitive peptidase is released from choroid or brain tissues.…”

Section: Control Bmxmentioning

confidence: 67%

Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep

Marshall

Shaltout

Pirro

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Antenatal betamethasone (BM) therapy accelerates lung development in preterm infants but may induce early programming events with long-term cardiovascular consequences. To elucidate these events, we developed a model of programming whereby pregnant ewes are administered BM (2 doses of 0.17 mg/kg) or vehicle at the 80th day of gestation and offspring are delivered at term. BM-exposed (BMX) offspring develop elevated blood pressure; decreased baroreflex sensitivity; and alterations in the circulating, renal, and brain renin-angiotensin systems (RAS) by 6 mo of age. We compared components of the choroid plexus fourth ventricle (ChP4) and cerebral spinal fluid (CSF) RAS between control and BMX male offspring at 6 mo of age. In the choroid plexus, high-molecular-weight renin protein and ANG I-intact angiotensinogen were unchanged between BMX and control animals. Angiotensin-converting enzyme 2 (ACE2) activity was threefold higher than either neprilysin (NEP) or angiotensin 1-converting enzyme (ACE) in control and BMX animals. Moreover, all three enzymes were equally enriched by approximately 2.5-fold in ChP4 brush-border membrane preparations. CSF ANG-(1-7) levels were significantly lower in BMX animals (351.8 ± 76.8 vs. 77.5 ± 29.7 fmol/mg; P < 0.05) and ACE activity was significantly higher (6.6 ± 0.5 vs. 8.9 ± 0.5 fmol·min(-1)·ml(-1); P < 0.05), whereas ACE2 and NEP activities were below measurable limits. A thiol-sensitive peptidase contributed to the majority of ANG-(1-7) metabolism in the CSF, with higher activity in BMX animals. We conclude that in utero BM exposure alters CSF but not ChP RAS components, resulting in lower ANG-(1-7) levels in exposed animals.

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“…Use of CSF, a nervous system indicator of growing interest in ALS (Sussmuth et al, 2008; Gladman et al, 2012; Mendonca et al, 2012; Tarasiuk et al, 2012; von Neuhoff et al, 2012; Wilson et al, 2013; Winer et al, 2013), as a biomarker of exposure rather than peripheral indicators such as blood or toenails is an additional strength of the present study. In our recent study on the relation among CSF and other indicators in neurologically healthy subjects (Solovyev et al, 2013), positive associations between CSF and blood levels were found only for Se-GPx, Se-TrxR and Se-HAS, while there was little or no correlation between CSF and blood levels for other organic forms such as SePP, for selenite and selenate (correlation coefficients −0.03 and 0.23, respectively, unpublished data by N. S. and B. M.), and total Se.…”

Section: Discussionmentioning

confidence: 99%

“…We conducted a case-control study to examine the hypothesis that Se species and particularly the inorganic ones are associated with ALS risk by using a CNS biomarker of exposure, cerebrospinal fluid (CSF), which appears to play a key role in assessing exposure to etiopathogenetic and therapeutic factors in this disease (Tarasiuk et al, 2012; von Neuhoff et al, 2012; Wilson et al, 2013; Winer et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Cerebrospinal fluid of newly diagnosed amyotrophic lateral sclerosis patients exhibits abnormal levels of selenium species including elevated selenite

et al. 2013

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Exposure to selenium, and particularly to its inorganic forms, has been hypothesized as a risk factor for amyotrophic lateral sclerosis (ALS), a fast progressing motor neuron disease with poorly understood etiology. However, no information is known about levels of inorganic and some organic selenium species in the central nervous system of ALS patients, and recent observations suggest that peripheral biomarkers of exposure are unable to predict these levels for several Se species including the inorganic forms. Using a hospital-referred cases-control series and advanced selenium speciation methods, we compared the chemical species of selenium in cerebrospinal fluid from thirty-eight ALS patients to those of thirty-eight reference neurological patients matched on age and gender. We found that higher concentrations of inorganic selenium in the form of selenite and of human serum albumin-bound selenium were associated with increased ALS risk (relative risks 3.9 (95% confidence interval 1.2–11.0) and 1.7 (1.0–2.9) for 0.1µg/l increase). Conversely, lower concentrations of selenoprotein P-bound selenium were associated with increased risk (relative risk 0.2 for 1µg/l increase, 95% confidence interval 0.04–0.8). The associations were stronger among cases age 50 years or older, who are postulated to have lower rates of genetic disease origin. These results suggest that excess selenite and human serum albumin bound-selenium and low levels of selenoprotein P-bound selenium in the central nervous system, which may be related, may play a role in ALS etiology.

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Measurement of cystatin C functional activity in the cerebrospinal fluid of amyotrophic lateral sclerosis and control subjects

Cited by 31 publications

References 29 publications

Proteomic Analysis of Cerebrospinal Fluid in Canine Cervical Spondylomyelopathy

Proteomic Analysis of Cerebrospinal Fluid in Canine Cervical Spondylomyelopathy

Antenatal betamethasone exposure is associated with lower ANG-(1–7) and increased ACE in the CSF of adult sheep

Cerebrospinal fluid of newly diagnosed amyotrophic lateral sclerosis patients exhibits abnormal levels of selenium species including elevated selenite

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