Amyotrophic Lateral Sclerosis Multiprotein Biomarkers in Peripheral Blood Mononuclear Cells

Abstract

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.Methodology/Principal FindingsWe used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%), and from patients with neurological disorders that may resemble ALS (91%), between two levels of disease severity (90%), and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.Conclusions/SignificanceOur results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms.

Reduced Calreticulin Levels Link Endoplasmic Reticulum Stress and Fas-Triggered Cell Death in Motoneurons Vulnerable to ALS

“…Unfortunately, using an ELISA test, we were unable to detect CRT release in the culture medium of motoneurons. Interestingly, a study aiming to identify biomarkers showed a doubling of CRT amount in ALS patients' peripheral blood mononuclear cells compared with controls (Nardo et al, 2011).…”

TDP-43 regulates endogenous retrovirus-K viral protein accumulation

“…Page 5 of 35 Nardo et al, 2011;Noto et al, 2011;Pare et al, 2015). Only 5-10% of familial and 1% of sporadic ALS cases carry TDP-43 mutations (Lattante et al, 2012;Millecamps et al, 2010), yet wild-type TDP-43 is incorrectly processed in the majority of patients with ALS (Janssens and Van Broeckhoven, 2013).…”

Calcium-dependent protein folding in amyotrophic lateral sclerosis

“…In ALS, the stress responsive protein Erp57 is upregulated in the spinal cord [47]. Moreover, in peripheral blood mononuclear cells of ALS patients, the level of Erp57 can be used to discriminate between patients with high and low disease severity [82]. Secondly, knock-out of calreticulin and calnexin is associated with motor impairment.…”