Clinically relevant intronic splicing enhancer mutation in myelin proteolipid protein leads to progressive microglia and astrocyte activation in white and gray matter regions of the brain

Adam D. Bachstetter, Scott J. Webster, Linda J. Van Eldik, Franca Cambi

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Introduction: Mutations in proteolipid protein (PLP), the most abundant myelin protein in the CNS, cause the X-linked dysmyelinating leukodystrophies, Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2). Point mutations, deletion, and duplication of the PLP1 gene cause PMD/SPG2 with varying clinical presentation. Deletion of an intronic splicing enhancer (ISEdel) within intron 3 of the PLP1 gene is associated with a mild form of PMD. Clinical and preclinical studies have indicated that mutations in myelin proteins, including PLP, can induce neuroinflammation, but the temporal and spatial onset of the reactive glia response in a clinically relevant mild form of PMD has not been defined.Methods: A PLP-ISEdel knockin mouse was used to examine the behavioral and neuroinflammatory consequences of a deletion within intron 3 of the PLP gene, at two time points (two and four months old) early in the pathological progression. Mice were characterized functionally using the open field task, elevated plus maze, and nesting behavior. Quantitative neuropathological analysis was for markers of astrocytes (GFAP), microglia (IBA1, CD68, MHCII) and axons (APP). The Aperio ScanScope was used to generate a digital, high magnification photomicrograph of entire brain sections. These digital slides were used to quantify the immunohistochemical staining in ten different brain regions to assess the regional heterogeneity in the reactive astrocyte and microglial response.Results: The PLP-ISEdel mice exhibited behavioral deficits in the open field and nesting behavior at two months, which did not worsen by four months of age. A marker of axonal injury (APP) increased from two months to four months of age. Striking was the robust reactive astrocyte and microglia response which was also progressive. In the two-month-old mice, the astrocyte and microglia reactivity was most apparent in white matter rich regions of the brain. By four months of age the gliosis had become widespread and included both white as well as gray matter regions of the brain.Conclusions: Our results indicate, along with other preclinical models of PMD, that an early reactive glia response occurs following mutations in the PLP gene, which may represent a potentially clinically relevant, oligodendrocyte-independent therapeutic target for PMD.

Original languageEnglish
Article number911
JournalJournal of Neuroinflammation
StatePublished - Dec 5 2013

Bibliographical note

Funding Information:
We thank Danielle Goulding for excellent technical assistance. This research was supported in part by Pelizaeus-Merzbacher Disease Foundation (ADB, FC); NIH/NIA (K99AG044445 to ADB); and NIH/NINDS (R01NS053905 and ARRA R01NS053905-03S to FC).


  • Leukodystrophies
  • Neuroinflammation
  • Pelizaeus-Merzbacher disease

ASJC Scopus subject areas

  • General Neuroscience
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience


Dive into the research topics of 'Clinically relevant intronic splicing enhancer mutation in myelin proteolipid protein leads to progressive microglia and astrocyte activation in white and gray matter regions of the brain'. Together they form a unique fingerprint.

Cite this