Similar to other neurodegenerative disorders, the onset of progressive MS is related to age, a factor known to amplify neurodegeneration. Recent studies have shown that exposure of aged mice to a young blood circulation through parabiosis or administration of young blood plasma (plasma from 3-month-old mice) reverses cognitive deficits observed with normal ageing.
We aimed to search for soluble factors in the serum of patients with progressive MS that are affected by age and are differentially decreased in patients compared to healthy controls (HC) of similar age.
Protein levels were determined in serum samples from a cohort of 30 untreated MS patients (15 patients with secondary progressive MS - SPMS - and 15 with primary progressive MS - PPMS) and 25 HC. Progressive MS patients were classified according to age and clinical characteristics into the following three groups (each group containing 10 patients, 5 with SPMS and 5 with PPMS): (i) 40 ± 3 years old, disease duration <10 years, EDSS <4.5; (ii) 50 ± 3 years old, disease duration between 10-20 years, EDSS between 4.5-6; and (iii) 60 ± 3 years old, disease duration >20 years, EDSS >6.5. HC were classified based on age into the following groups (each group containing 5 individuals): 20, 30, 40, 50, and 60 ± 3 years old. To maximize the breadth and depth of serum proteome coverage, the top 70 abundant proteins in serum were depleted. Afterwards, samples were subjected to mass spectrometry.
After depletion of the most abundant proteins in serum, a total of 2,059 molecules were detected in all 55 samples. The maSigPro package (R Bioconductor) was used to identify proteins with significantly divergent expression profiles as a function of time. A quadratic regression model was fit for each molecule and 823 proteins, among the 2059 analyzed, were found differentially expressed (FDR < 0.05) between the MS group and HC. The serum levels of the following proteins were significantly decreased by ageing in progressive MS patients compared with HC and were selected for further studies: PLXDC2, Neudesin, Myostatin, Myocilin, and EMMPRIN.
Protein expression profiling associated with ageing in progressive MS patients and HC lead to the identification of number of promising candidates associated with neurotrophic functions, myelination, and nervous system development. Results obtained by mass spectrometry need to be validated by targeted immunoassays.