Neuroinflammation-Related Proteins NOD2 and Spp1 Are Abnormally Upregulated in Amyotrophic Lateral Sclerosis

Abstract

Background and ObjectivesAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of unknown etiology and poorly understood pathophysiology. There is no specific biomarker either for diagnosis or prognosis. The aim of our study was to investigate differentially expressed proteins in the CSF and serum from patients with ALS to determine their role in the disease process and evaluate their utility as diagnostic or prognostic biomarkers.MethodsWe performed mass spectrometry in the CSF from 3 patients with ALS and 3 healthy controls (HCs). The results were compared with motor cortex dysregulated transcripts obtained from 11patients with sporadic ALS and 8 HCs. Candidate proteins were tested using ELISA in the serum of 123 patients with ALS, 30 patients with Alzheimer disease (AD), 28 patients with frontotemporal dementia (FTD), and 102 HCs. Patients with ALS, AD, and FTD were prospectively recruited from January 2003 to December 2020. A group of age-matched HCs was randomly selected from the Sant Pau Initiative on Neurodegeneration cohort of the Sant Pau Memory Unit.ResultsNucleotide-binding oligomerization domain–containing protein 2 (NOD2) and osteopontin (Spp1) were differentially expressed in the CSF and the motor cortex transcriptome of patients with ALS compared with that in HCs (p< 0.05). NOD2 and Spp1 levels were significantly higher in sera from patients with ALS than in HCs (p< 0.001). Receiver operating characteristic analysis showed an area under the curve of 0.63 for NOD2 and 0.81 for Spp1. NOD2 levels were significantly lower in patients with AD and FTD than in patients with ALS (p< 0.0001), but we found no significant differences in Spp1 levels between patients with ALS, AD (p= 0.51), and FTD (p= 0.42). We found a negative correlation between Spp1 levels and ALS functional rating scale (r= −0.24,p= 0.009).DiscussionOur discovery-based approach identified NOD2 as a novel biomarker in ALS and adds evidence to the contribution of Spp1 in the disease process. Both proteins are involved in innate immunity and autophagy and are increased in the serum from patients with ALS. Our data support a relevant role of neuroinflammation in the pathophysiology of the disease and may identify targets for disease-modifying treatments in ALS. Further longitudinal studies should investigate the diagnostic and prognostic value of NOD2 and Spp1 in clinical practice.

A patient-derived amyotrophic lateral sclerosis blood-brain barrier cell model reveals focused ultrasound-mediated anti-TDP-43 antibody delivery

“…Interstingly, while ALS is commonly associated with an increased proinflammatory profile (1,23,39,70), we found a decreased (P<0.05) expression of proinflammatory marker genes, IL6 and TNF, in sporadic ALS iBECs compared to healthy donor cells, with IL6 demonstrating also reduced (P<0.0001) expression in sporadic ALS iBECs compared to C9orf72 ALS iBECs (Figure 5A).…”

Small peptide fingerprint (peptidomics) of Amyotrophic Lateral Sclerosis in CSF

“…Moreover, it has also been found differentially expressed in microglia in an ALS rodent model and been suggested to contribute to the late stage of neurodegeneration by OPN induced MMP-9 up-regulation, CD44-mediated astrocyte migration and microglial phagocytosis 23,39 . Upregulation in the CSF has been reported by several proteomic studies before 24,34 . We confirmed this finding by proofing a massively upregulated peptide fragment 87061 in parallel with a low-abundant fragment 16933, which seems to be of regulative nature.…”

Altered Metabolism and DAM-signatures in Female Brains and Microglia with Aging

“…However, significant differences were noted between sex-related genes such as Xist , Ddx3y , and Eif2s3y that are located on the X and Y chromosome ( Figure 2A ). Interestingly, in the 20-month mice, we observed significant differences in genes associated with AD pathology and disease-associated microglia (DAMs) (Olah et al, 2020), such as Spp1 , Clu , and ApoE (de Luna et al, 2023; De Schepper et al, 2023; Kim et al, 2022) ( Figure 2B ). In addition, differential expression of X- and Y-linked genes like Ddx3y , Uty , Kdm5d , and Eif2s3y persisted with aging ( Figure 2B ).…”