Altered secretory and neuroprotective function of the choroid plexus in progressive multiple sclerosis

Acta Neuropathol Commun. 2020 Mar 19;8(1):35. doi: 10.1186/s40478-020-00903-y.

Abstract

The choroid plexus (CP) is a key regulator of the 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, we studied transcriptomic alterations of the human CP in progressive MS and non-neurological disease controls using RNA sequencing. 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. In an ex vivo CP explant model, a subset of the upregulated genes responded in a similar way to hypoxic conditions. Our results suggest a deregulation of the Hypoxia-Inducible Factor (HIF)-1 pathway in progressive MS CP. Importantly, cerebrospinal fluid levels of the hypoxia-responsive secreted peptide PAI-1 were higher in MS patients with high disability relative to those with low disability. These findings provide for the first time a complete overview of the CP transcriptome in health and disease, and suggest that the CP environment becomes hypoxic in progressive MS patients, highlighting the altered secretory and neuroprotective properties of the CP under neuropathological conditions. Together, these findings provide novel insights to target the CP and promote the secretion of neuroprotective factors into the CNS of progressive MS patients.

Keywords: Cerebrospinal fluid (CSF); Choroid plexus; Hypoxia; Multiple sclerosis (MS); PAI-1; RNA-sequencing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenomedullin / cerebrospinal fluid
  • Adrenomedullin / genetics
  • Adult
  • Aged
  • Case-Control Studies
  • Choroid Plexus / metabolism*
  • Female
  • Gene Expression Profiling
  • Gene Ontology
  • Glycoproteins / cerebrospinal fluid
  • Glycoproteins / genetics
  • Humans
  • Hypoxia / genetics*
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Intercellular Signaling Peptides and Proteins / cerebrospinal fluid
  • Intercellular Signaling Peptides and Proteins / genetics
  • Lateral Ventricles
  • Male
  • Metallothionein / genetics
  • Middle Aged
  • Multiple Sclerosis, Chronic Progressive / cerebrospinal fluid
  • Multiple Sclerosis, Chronic Progressive / genetics*
  • Multiple Sclerosis, Relapsing-Remitting / cerebrospinal fluid
  • Multiple Sclerosis, Relapsing-Remitting / genetics*
  • Neuroprotection / genetics*
  • Neurosecretion / genetics*
  • Plasminogen Activator Inhibitor 1 / cerebrospinal fluid
  • Plasminogen Activator Inhibitor 1 / genetics
  • RNA, Antisense / genetics
  • RNA, Long Noncoding
  • RNA-Seq

Substances

  • ADM protein, human
  • Glycoproteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Intercellular Signaling Peptides and Proteins
  • MT1A protein, human
  • Plasminogen Activator Inhibitor 1
  • RNA, Antisense
  • RNA, Long Noncoding
  • STC2 protein, human
  • Adrenomedullin
  • Metallothionein