018 – TGFB1-mediated gliosis in multiple sclerosis spinal cords is favored by the physiological expression of regionalization homeobox genes and the age-dependent decline in androgen receptor ligands
Serge Nataf (1) – Marine Guillen (1) – Laurent Pays (1)
University Claude Bernard Lyon-1, CarMeN Laboratory, INSERM 1060, INRA 1397, INSA Lyon, Bank of Tissues and Cells, Hospices Civils de Lyon, Lyon, France (1)
In multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord (SC) functions slowly deteriorate beyond age 40. Paradoxically, neuropathological studies demonstrated a lower inflammatory burden in MS SCs as compared to MS brains. However, in the SC of PPMS (primary progressive MS) or SPMS (secondary progressive MS) patients, we previously showed that despite the relative paucity of active lesions, large areas of incomplete demyelination extend distance away from plaque borders. Moreover, such peculiar tissue alterations are characterized by an extensive gliosis and a unique TGFB1 (Transforming Growth Factor Beta 1) genomic signature. It appears thus that progression in SPMS or PPMS patients might result from a regionally-controlled SC process that would be aggravated by aging. Here, we attempted to determine whether region- and age-specific physiological parameters could promote the progression of SC periplaques in MS patients beyond age 40. An analysis of transcriptomics databases showed that, under normal or pathological conditions, a highly significant number of homeobox (HOX) genes are overexpressed in the human SC as compared to the brain. Interestingly, a survey of the human proteome allowed mapping protein-protein interactions connecting SC-overexpressed HOX proteins with 2 progliotic transcription factors, namely SOX2 and the TGF-beta signaling molecule SMAD1. This finding suggests that the physiological SC overexpression of HOX genes could favor SOX2/SMAD1-mediated astrocytosis in MS SCs. On this basis, we hypothesized that the age-dependent decline in androgen receptor ligands, which exert known anti-gliotic effects, could amplify such a region-specific mechanism. Supporting this view, a manual curation of previously published promoter analysis experiments showed that SOX2 and several members of the TGFB1 pathway are indeed transcriptionally repressed by the androgen receptor (AR). We propose that in SPMS or PPMS patients beyond age 40, the physiological SC overexpression of HOX proteins combined with the physiological decline in AR ligands favor the slow progression of TGFB1-triggered gliosis.