Cerebrospinal fluid and serum miRNAs in sporadic amyotrophic lateral sclerosis: potential biomarkers and pathogenic role

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder. Since there is no diagnostic laboratory test, the identification of biomarkers specific for ALS could be of fundamental importance in clinical practice. In the last few years microRNAs (miRNAs) have aroused great interest as potential biomarkers for neurodegenerative diseases in serum and cerebrospinal fluid (CSF) samples. In particular, miRNAs detected in (CSF) better reflect brain pathological conditions than those present in other body fluids but its withdrawal is more invasive compare to blood. The aim of the study was to identify a serum and CSF miRNA set that could differentiate ALS from non-ALS condition. We performed miRNA profiling in CSF and serum from ALS patients (n=24; eight with C9orf72 expansion) and unaffected control subjects (n=24) by quantitative reverse transcription PCR (q-RT-PCR) on a 372-miRNA PCR array. Thirteen downregulated miRNAs and one upregulated miRNAs and eighteen deregulated miRNAs, one downregulated and two upregulated were identified in ALS from CSF and serum samples respectively. In validation experiments, among the deregulated miRNAs, eight were confirmed as significantly deregulated in CSF samples from patients compared to controls and three were confirmed in serum samples. No significant differences were observed between ALS patients with or without C9orf72 expansion neither for CSF nor for serum samples. The Receiver Operator Characteristic (ROC) curve analyses revealed for CSF samples the highest diagnostic accuracy as potential ALS biomarkers for the upregulated miR181a-5p and the downregulated miR21-5p and miR15b-5p. The analyses of miR181a-5p/miR21-5p and miR181a-5p/miR15b-5p ratios were able to detect ALS with 90% and 85% sensitivity and 87% and 91% specificity, respectively, confirming the application potential of these molecules as disease biomarkers. Moreover, pathway analysis indicated that these deregulated miRNAs are implicated in apoptotic way, providing important insight into disease processes responsible for motor neuron degeneration.