Multi-Omics Approach to Elucidate Cerebrospinal Fluid Changes in Dogs with Intervertebral Disc Herniation

Abstract

Herniation of the intervertebral disc (IVDH) is the most common cause of neurological and intervertebral disc degeneration-related diseases. Since the disc starts to degenerate before it can be observed by currently available diagnostic methods, there is an urgent need for novel diagnostic approaches. To identify molecular networks and pathways which may play important roles in intervertebral disc herniation, as well as to reveal the potential features which could be useful for monitoring disease progression and prognosis, multi-omics profiling, including high-resolution liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and tandem mass tag (TMT)-based proteomics was performed. Cerebrospinal fluid of nine dogs with IVDH and six healthy controls were used for the analyses, and an additional five IVDH samples were used for proteomic data validation. Furthermore, multi-omics data were integrated to decipher a complex interaction between individual omics layers, leading to an improved prediction model. Together with metabolic pathways related to amino acids and lipid metabolism and coagulation cascades, our integromics prediction model identified the key features in IVDH, namely the proteins follistatin Like 1 (FSTL1), secretogranin V (SCG5), nucleobindin 1 (NUCB1), calcitonin re-ceptor-stimulating peptide 2 precursor (CRSP2) and the metabolites N-acetyl-D-glucosamine and adenine, involved in neuropathic pain, myelination, and neurotransmission and inflammatory response, respectively. Their clinical application is to be further investigated. The utilization of a novel integrative interdisciplinary approach may provide new opportunities to apply innovative diagnostic and monitoring methods as well as improve treatment strategies and personalized care for patients with degenerative spinal disorders.

TMT-Based Proteomics Analysis of Senescent Nucleus Pulposus from Patients with Intervertebral Disc Degeneration

“…Although cellular senescence can cause IDD progression, the underlying mechanism is unclear [3,[7][8][9]. Proteomics studies are widely used to identify potential therapeutic targets for various diseases, including IDD [25,26]. In this study, we collected aging NP tissues from individuals with IDD for proteomics analysis and experimental validation.…”

Roles of organokines in intervertebral disc homeostasis and degeneration

“…Follistatin-like-1(FSTL-1) is a kind of myokine and cardiokine modulating immune responses, cell proliferation, and differentiation through binding to TLR-4, Wnt receptors, and various growth factors. FSTL-1 has an adverse effect on disc homeostasis, accompanied by increased concentrations in the serum of IVDD patients, discs of rats with IVDD, and the cerebrospinal fluid of dogs with IVDD ( 125 , 141 ). Mechanistically, FSTL-1 promotes NP cell inflammation by activating the MAPK, Smads, or NF-κB signaling pathway ( 125 , 141 ).…”

“…FSTL-1 has an adverse effect on disc homeostasis, accompanied by increased concentrations in the serum of IVDD patients, discs of rats with IVDD, and the cerebrospinal fluid of dogs with IVDD ( 125 , 141 ). Mechanistically, FSTL-1 promotes NP cell inflammation by activating the MAPK, Smads, or NF-κB signaling pathway ( 125 , 141 ). Interestingly, the knockout of FSTL-1 during embryonic development leads to a decrease in vertebral cartilage and matrix anabolism, indicating its fundamental role in early IVD formation ( 142 ).…”

Possible Association of Nucleobindin-1 Protein with Depressive Disorder in Patients with HIV Infection

“…Importantly, it is believed to be a novel pan-neuronal calcium handling marker [ 7 ], associated with cancers [ 8 ], and stimulating insulin secretion [ 9 ]. According to the literature, NUCB1 protein is implicated in Alzheimer’s disease [ 10 , 11 ], other neurodegenerative diseases, or cellular processes known to be dysregulated early in tauopathy pathogenesis [ 12 ] such as synaptic plasticity, proteostasis, glucose metabolism, and mitochondrial function. Recently, a paper indicated that an adult-viable mutant that completely disrupts the G protein α-subunit binding and activates NUCB1 plays a neuroprotective role in the Drosophila model [ 13 ] of neurodegenerative disease.…”