Proteomic analysis of plasma from Portuguese patients with familial amyotrophic lateral sclerosis

Abstract

In ALS, the identification of abnormal proteins in biological fluids might be useful for the understanding of the ethiopathogenesis of the disease. Furthermore, it can provide biomarkers useful for diagnosis, to monitor disease progression and to study the effect of drugs. Plasma is a suitable fluid for screening such targets since blood collection is a relatively simple procedure. In this study, proteomic techniques consisting of two-dimensional gel electrophoresis and matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF MS) have been used for the analysis of plasma from a group of Portuguese familial ALS (FALS) patients not carrying SOD1 mutations, age-matched healthy controls, sporadic ALS patients and controls with other muscular disorders. Most relevant was the finding in the FALS patients of an isoform of vitamin D-binding protein (DBP) at pI 5.2, identified as GC2 by liquid chromatography electrospray ionization-TOF MS. GC2 was absent from the healthy controls. Concomitantly, decrease of more acidic isoforms of DBP was observed for the FALS patients. The results suggested that the GC2 polymorphism of DBP could constitute a risk factor for ALS.

Proteomic Analysis of Dynein-Interacting Proteins in Amyotrophic Lateral Sclerosis Synaptosomes Reveals Alterations in the RNA-Binding Protein Staufen1

“…A number of proteomic screens have also attempted to identify novel players in the pathology of ALS (67), and to provide detectable biomarkers in biological fluids, such as plasma (68), cerebrospinal fluid, and brain extracellular fluid (69) of human patients. Transport defects are common to the various genetic etiologies in ALS (70), pointing to ALS as a spatiotemporal mislocalization disease, including mislocalization of mRNA (reviewed in (12)).…”

Common variants of the vitamin D binding protein gene and adverse health outcomes

“…Gc2-2 individuals were overrepresented in sero-negative contacts of AIDS patients ( p  < 0.05).Pronk et al212 447 (96 AIDS patients and 351 homosexual men86NetherlandsCaucasian a Gc1F, Gc1S, Gc2NSPutkonen n et al218 125 (85 AIDS patients and 40 couples with 1 infected partner)3394SwedenCaucasian a Gc1F, Gc1S, Gc2NSRosberger et al227 1211011United StatesCaucasians and African AmericansGc1F, Gc1S, Gc2NSRheumatoid FeverBahr et al208 3990KuwaitArabicGc1F, Gc1S, Gc2An association was observed between Gc2 allele with rheumatic fever ( p  = 0.0024); 56% of all rheumatic fever patients were carriers of Gc2 allele.Tuberculosis (TB)Bahr et al208 4190KuwaitArabicGc1F, Gc1S, Gc2No association with GC alleles and TB, although an association was observed between Gc2 allele with rheumatic fever ( p  = 0.0024); 56% of all rheumatic fever patients were carriers of Gc2 allele.Martineau et al206 123 (United Kingdom); 130 (Brazil); 281 (South Africa)140 (United Kingdom); 78 (Brazil); 182 (South Africa)United KingdomVaried based on study location d Gc1F, Gc1S, Gc2Associations between GC polymorphism and TB only observed in Gujarati Asians from United Kingdom. Gc2-2 associated with susceptibility to active TB compared to wild type (Gc1-1): OR = 2.81 for Gc2-2 versus Gc1-1 (CI = 1.19–6.66, p  = 0.009) No associations were observed in the populations from Brazil and or South Africa. Neurodegeneration Amyotrophic Lateral Sclerosis (ALS)Palma et al182 11 (7 ALS, 4 other muscular disorders)…”

“…Mutations in the cytosolic superoxide dismutase ( SOD1 ) gene have been associated with ALS, but these account for less than 20% of all familial ALS (FALS)181. In Portuguese patients with FALS, proteomic analysis showed that the Gc-2 phenotype (436 K) was overrepresented in comparison to healthy controls182. The role of DBP in ALS is not known, but it is tempting to speculate that motor neuron damage resulting in the systemic release of actin and ensuing intravascular coagulation and local hypoxia-induced oxidative damage may be mitigated by the actin-scavenging properties of DBP.…”

Biological and Neuroimaging Biomarkers for Amyotrophic Lateral Sclerosis: 2013 and Beyond

“…The analytical platform often used in ALS studies is based on 2D gel electrophoresis or liquid chromatography to separate proteins and matrixassisted laser desorption/ionization to generate ions in combination with mass analyzers, such as time-of-flight. [82] Kumar et al Transport of vitamin D sterols and actin-scavenging system [168] ↑: Higher metabolite levels in ALS patients compared with controls (i.e., ratio of metabolite levels in ALS:controls >1); ↓: Table 3 shows the chief proteomics studies in ALS. Cystatin C, a widely expressed cysteine protease inhibitor that is found in Bunina bodies on histopathological examination [86], is identified in most proteomics studies (Table 3) and in numerous targeted studies.…”