Metal and proteomic analysis of sporadic ALS patients with common geographical origin

Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disorder characterized by selective degeneration of both upper and lower motor neurons in the brain, brainstem, and spinal cord. This results in paralysis due to muscle weakness and atrophy, leading to death in 3-5 years. Genetic and environmental factors are involved in the pathogenesis of the disease and metals metabolism have been linked to ALS. This study enrolled seven patients and five controls (age matched, living in the same geographical area). For metal quantitation, samples of serum were analyzed by ICP-MS. For proteomic analyses, immobilized pH gradient covered the 4-10 and 3-7 pH range. Statistical analyses were carried out with Student's t-test and Artificial Neural Networks. Among the metals analyzed, As concentration resulted significantly lower in patients than in controls (p=0.007); Hg too was found in lower concentration in patients, but with a lower statistical significance (p=0.13). Higher concentration of Al in patients was detected (p=0.08). In this study, we were not able to confirm the higher concentrations of Ni and Pb in patients previously described in a smaller cohort. Our proteomics data show that APOA2 is decreased by 30% in patients with respect to controls. Furthermore, AHSG and SAP showed a significant decrease in patients with a story of more than 10 years of disease. Impaired metal homeostasis, attributable to environmental exposure, could lead to mineral overload. Besides promoting oxidative stress, metals can compete for the binding sites of metal-containing proteins, such as those containing iron-sulfur clusters. At present, no literature data link APOA2 to ALS, but the fact that its mRNA is processed by TDP43, provides a possible connection with the disease. The proteins differentially expressed belong to the group of Acute Phase Reaction proteins, possibly linking ALS to a chronic inflammation status. Further experiments are still ongoing.