Serum Proteome in a Sporadic Amyotrophic Lateral Sclerosis Geographical Cluster

Abstract

This study is meant to characterize the serum proteome in a small geographical cluster of sporadic ALS subjects originating from a restricted geographical area and sharing the same environmental exposure, in a broader context of evaluating the relevance of environmental factors to disease onset, status, and progression. An Artificial Neural Network based software is used to compare the relative abundance of proteins identified as different (by means of bi-dimensional electrophoresis and mass spectrometry) in the serum proteome of patients and age-matched healthy controls. The patient's group is characterized by altered levels of acute phase reactants and of proteins involved in lipid homeostasis, along with over-representation of the APOE*4 allele. Characterization of the serum proteome in a small cluster of sporadic ALS patients, originating from a geographically restricted area with a high prevalence of the disease and evaluation of the results with software based on artificial neural networks, highlights the association of the relative abundance of some proteins (most notably, acute phase reactants and lipid homeostasis proteins) with the disease presence and status.

The Need for Biomarkers in the ALS–FTD Spectrum: A Clinical Point of View on the Role of Proteomics

“…The authors identified the 20 most changed proteins, which were mainly represented by proangiogenic and growth factors, thus suggesting that altered glial activation and blood–brain barrier leakage may be involved in ALS pathogenesis. The detection of differences in the serum levels of acute phase reactants in ALS patients than in controls has been reported by another study [ 114 ], together with changes in lipid homeostasis proteins, thus supporting the hypothesis of a metabolic shift towards increased peripheral use of lipids in ALS patients and suggesting the involvement of lipid homeostasis in the disease [ 114 ]. Serum protein changes were also correlated with specific characteristics of the disease.…”

Lipid Biomarkers for Amyotrophic Lateral Sclerosis

“…The identification of APOE ε4 as a risk factor for Alzheimer's disease represented a major breakthrough in the field [(26), and references therein]. On the contrary, most studies on ALS did not observe any association of APOE ε4 with an increased risk (27–30), excepted some recent findings (31). Additional reports showed complex interactions between particular APOE alleles and other genetic or physiopathological variables.…”

Multi-Study Proteomic and Bioinformatic Identification of Molecular Overlap between Amyotrophic Lateral Sclerosis (ALS) and Spinal Muscular Atrophy (SMA)

“…A total of 33 proteomic studies of ALS were eligible for comparison (Table S1) [20,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62]. As expected, the number of differentially expressed proteins identified in studies correlated with the sensitivity of the method used, with label-free technologies having identified by far the greatest number of protein changes compared to 2D-gel approaches.…”

“…Both in vivo and in vitro models of ALS were used in analyses, and samples from animal models and ALS patients were equally represented across studies (Table S1). Samples were derived from a range of sources, including ALS patient cerebrospinal fluid (CSF) [20,31,32,33,34,35,36,37,38,39,40], patient serum [41], a range of cell models [42,44,57,59], ALS patient muscle [45,46], ALS patient blood mononuclear cells (PBMC) [48], ALS patient spinal cord [61], ALS patient prefrontal cortex [62], and tissues/cells from various mouse and rat models of ALS including astrocytes [47], skeletal muscle [53], ventral roots [50], embryonic motor neurons [51], spinal cord [43,49,52,54,55,56,58], and hippocampus [60].…”

“…Thus, studies that utilized cells/tissues were compared separately to those that examined biofluids. Comparison across the 12 proteomic studies that examined biofluids from ALS patients [20,31,32,33,34,35,36,37,38,39,40,41] identified 11 proteins that were consistently changed in the same direction across at least two studies (Table S2). Of these, one protein—cystatin C—was decreased in expression across four separate studies [35,37,38,39] and one protein—chitinase 3-like protein 1—was increased in expression across three separate studies [32,34,41].…”