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Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. One of the peculiar clinical characteristics of ALS is the wide distribution in age of onset, which is probably caused by different combinations of intrinsic and exogenous factors. We investigated whether these modifying factors are converging into common pathogenic pathways leading either to an early or a late disease onset. This would imply the identification of phenotypic biomarkers, that can distinguish the two populations of ALS patients, and of relevant pathways to consider in a therapeutic intervention. Toward this aim a differential proteomic analysis was performed in peripheral blood mononuclear cells (PBMC) from a group of 16 ALS patients with an age of onset ≤55 years and a group of 16 ALS patients with an age of onset ≥75 years, and matched healthy controls. We identified 43 differentially expressed proteins in the two groups of patients. Gene ontology analysis revealed that there was a significant enrichment in annotations associated with protein folding and response to stress. We next validated a selected number of proteins belonging to this functional group in 85 patients and 83 age- and sex-matched healthy controls using immunoassays. The results of the validation study confirmed that there was a decreased level of peptidyl-prolyl cis-trans isomerase A (also known as cyclophilin A), heat shock protein HSP 90-alpha, 78 kDa glucose-regulated protein (also known as BiP) and protein deglycase DJ-1 in PBMC of ALS patients with an early onset. Similar results were obtained in PBMC and spinal cord from two SOD1G93A mouse models with an early and late disease onset. This study suggests that a different ability to upregulate proteins involved in proteostasis, such as foldase and chaperone proteins, may be at the basis of a different susceptibility to ALS, putting forward the development of therapeutic approaches aiming at boosting the protein quality control system.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration
The overrepresentation test performed against a reference list of lymphocyte/monocyte proteins, identified in 2D-based proteomic studies, indicated response to stress as one of the most significantly enriched (p = 0.03; fold = 2.5) biological processes. This suggested that proteins associated with these molecular functions and biological processes (Table 3), such as peptidylprolyl cis-trans isomerase A (PPIA), HSP 90alpha (HSP90), GRP78, ERp57, and DJ-1, were attracting candidate phenotypic biomarkers to further validate in a larger and well-characterized cohort of patients with early and late disease onset
It has been reported that exposure to certain toxins lead to GRP78 downregulation (Yang et al, 2000; Namba et al, 2010). These data suggest that a failure in the response to stress and a reduced ability to upregulate protective proteins may increase susceptibility to ALS. This is in agreement with the fact that vulnerable motor neurons have a high threshold for induction of the protective heat shock response and a higher sensitivity to ER stress (Batulan et al, 2003; Saxena et al, 2009)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive upper and lower motor neuron degeneration. The majority of ALS patients have disease onset between 55 and 75 years of age, patients with an age of onset 75 years do exist and represent, respectively, the 22% and the 16% of all patients, as recently reported in a large multicenter Italian study (Calvo et al, 2016) Several factors, both genetic and environmental/exogenous, have been reported to modify age of onset in patients and animal models of ALS. A mutant SOD1G93A mouse model of ALS on a 129Sv genetic background has an earlier age of onset than a SOD1G93A mouse model on a C57BL6 genetic background despite an equal expression of the mutant protein (Marino et al, 2015) These mice have faster disease progression and an intrinsic marked down-regulation of specific pathways involved in mitochondrial function and protein quality control (Nardo et al, 2013, 2016; Marino et al, 2015). In mutant SOD1 mice female showed a later onset than male and this delay further increased with exercise (Veldink et al, 2003)
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