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The choroid plexus in progressive multiple sclerosis presents hypoxia and secretory changes that may be related to neuroprotection

ABSTRACT: The choroid plexus (CP) is a key regulator of central nervous system (CNS) homeostasis through its secretory, immunological and barrier properties. Accumulating evidence suggests that the CP plays a pivotal role in the pathogenesis of multiple sclerosis (MS), but the underlying mechanisms remain largely elusive. To get a comprehensive view on the role of the CP in MS pathogenesis, we studied transcriptomic alterations of the human CP in progressive MS compared to controls using an RNA sequencing approach. We identified 17 genes with significantly higher expression in progressive MS patients relative to that in controls. Among them is the newly described long non-coding RNA HIF1A-AS3. Next to that, we uncovered disease-affected pathways related to hypoxia, secretion and neuroprotection, while only subtle immunological and no barrier alterations were observed. Three of the differentially expressed genes encode for secreted proteins, namely ADM, PAI-1 (SERPINE1) and STC2. Together, these findings provide novel insights to target the CP during MS and promote the secretion of neuroprotective factors into the CNS of progressive MS patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137619 | GEO | 2020/03/23

REPOSITORIES: GEO

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Project description:Multiple Sclerosis (MS) is a leading cause of incurable progressive disability in young adults caused by inflammation in the central nervous system (CNS) that triggers demyelination, glial cell dysfunction and irreversible neuro-axonal damage1. While considerable progress has been made in treating early inflammatory relapsing-remitting MS, the mechanisms underpinning the progressive stage remain largely unknown. The capacity of microglia, the CNS-resident phagocytes, to clear tissue debris is essential for both maintaining and restoring CNS homeostasis2,3 and this capacity diminishes with age4-6. Age strongly associates with the risk of developing progressive MS7,8. Herein we demonstrate that the recovery from inflammation is dependent on the ability of microglia to clear tissue debris and that blocking this process leads to development of progressive disease in a murine model of MS. Microglia-specific deletion of the general autophagy regulator Atg7, but not the canonical macroautophagy protein Ulk1, led to increased intracellular accumulation of phagocytosed myelin. This further associated with the alteration of the microglial phenotype towards that previously described in other neurodegenerative diseases2,3,9. Moreover, Atg7 deficient microglia showed striking similarities with microglia from aged wild type mice, which also demonstrated accumulation of myelin debris and inability to recover from MS-like disease. In contrast, the induction of autophagy using the disaccharide Trehalose in aged mice led to functional myelin clearance and remission from MS-like disease. Our results demonstrate that a non-canonical form of autophagy in microglia is responsible for myelin clearance and that impairment of this pathway markedly changes microglial phenotype and prevents recovery from MS-like disease. Importantly, we show that using a disaccharide ubiquitously found in plant-derived foods to boost autophagy in cells in which this process is naturally diminished can be utilized for therapeutic purposes.Project was run on 4 lanes with a 10M sequencing depth

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The choroid plexus in progressive multiple sclerosis presents hypoxia and secretory changes that may be related to neuroprotection

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