Azetidine-2-Carboxylic Acid-Induced Oligodendrogliopathy: Relevance to the Pathogenesis of Multiple Sclerosis

Author:

Sobel Raymond A12ORCID,Albertelli Megan3,Hinojoza Julian R12,Eaton Mary Jane12,Grimes Kevin V4,Rubenstein Edward5

Affiliation:

1. From the Laboratory Service, Veterans Affairs Health Care System, Palo Alto, California, USA

2. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

3. Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California, USA

4. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California, USA

5. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

Abstract

Abstract The naturally occurring imino acid azetidine-2-carboxylic acid (Aze) is consumed by humans and can be misincorporated in place of proline in myelin basic protein (MBP) in vitro. To determine Aze effects on the mammalian CNS in vivo, adult CD1 mice were given Aze orally or intraperitoneally. Clinical signs reminiscent of MBP-mutant mice occurred with 600 mg/kg Aze exposure. Aze induced oligodendrocyte (OL) nucleomegaly and nucleoplasm clearing, dilated endoplasmic reticulum, cytoplasmic vacuolation, abnormal mitochondria, and Aze dose-dependent apoptosis. Immunohistochemistry demonstrated myelin blistering and nuclear translocation of unfolded protein response (UPR)/proinflammatory molecules (ATF3, ATF4, ATF6, eIF2α, GADD153, NFκB, PERK, XBP1), MHC I expression, and MBP cytoplasmic aggregation in OL. There were scattered microglial nodules in CNS white matter (WM); other CNS cells appeared unaffected. Mice given Aze in utero and postnatally showed more marked effects than their dams. These OL, myelin, and microglial alterations are found in normal-appearing WM (NAWM) in multiple sclerosis (MS) patients. Thus, Aze induces a distinct oligodendrogliopathy in mice that recapitulates MS NAWM pathology without leukocyte infiltration. Because myelin proteins are relatively stable throughout life, we hypothesize that Aze misincorporation in myelin proteins during myelinogenesis in humans results in a progressive UPR that may be a primary process in MS pathogenesis.

Publisher

Oxford University Press (OUP)

Subject

Cellular and Molecular Neuroscience,Neurology (clinical),Neurology,General Medicine,Pathology and Forensic Medicine

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