Dissecting Sporadic ALS in a geographical cluster of patients: a multidisciplinary study

Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disorder that results in paralysis and leading to death in 3-5 years. Genetic and environmental factors are involved in the pathogenesis of this disease and metals metabolism has been linked to ALS. Proteomic studies are currently being performed to search for possible biomarkers. Here we present a study aimed at investigating different aspects of the disease, based on a multidisciplinary approach. The cohort of ALS patients that we analyzed includes seven patients, all originating from a common, restricted, geographical area and five matched controls. Environmental exposure is the same for all these subjects. SOD1, FUS, TDP43, C9ORF72 and APOE genotypes were evaluated. For metal quantitation, samples of serum and whole blood were analyzed by ICP-MS. For proteomic analyses, immobilized pH gradient covered the 4-10 and 3-7 pH range both in reducing and nonreducing conditions. Levels of DNA oxidation were evaluated by a comet assay. Statistical analyses were carried out with Student\u2019s t-test and Artificial Neural Networks. As concentration resulted significantly lower in patients than in controls ( Auto-CM analysis linked closely high concentrations of Al and Se to the ALS group. Levels of metals in whole blood have been correlated with levels in serum. Proteomics data show that some proteins related to Acute Phase Response (APR) and lipid homeostasis are decreased in patients. Apo\u3b54 allele is more represented in the patient\u2019s group than in controls\u2019. Impaired metal homeostasis, attributable to environmental exposure, could lead to mineral overload. Metals can compete for the binding sites of metal-containing proteins. The different expression of the APR proteins reported could be a reflection of the disease status of the subjects analyzed. Enrichment in Apo\u3b54 allele frequency in patients may provide a link between neurodegeneration and lipid metabolism disturbances