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

Area of Science:

• Neuroscience
• Biochemistry
• Pathology

Background:

• Azetidine-2-carboxylic acid (Aze), a naturally occurring imino acid, can be mistaken for proline.
• In vitro studies show Aze can be misincorporated into myelin basic protein (MBP].

Purpose of the Study:

• To investigate the in vivo effects of Aze on the mammalian central nervous system (CNS).
• To determine if Aze exposure can induce pathologies relevant to multiple sclerosis (MS).

Main Methods:

• Adult CD1 mice were administered Aze orally or intraperitoneally.
• Histopathological and immunohistochemical analyses were performed on CNS tissues.
• Effects were assessed in adult mice and those exposed in utero and postnatally.

Main Results:

• Aze exposure induced clinical signs similar to MBP-mutant mice.
• Oligodendrocytes (OLs) exhibited nucleomegaly, ER dilation, vacuolation, mitochondrial abnormalities, and apoptosis.
• Myelin blistering, nuclear translocation of UPR/proinflammatory molecules, and MBP aggregation in OLs were observed.
• Microglial nodules were present in CNS white matter (WM).
• In utero/postnatal exposure led to more severe alterations.

Conclusions:

• Aze induces a distinct oligodendrogliopathy in mice, recapitulating key features of normal-appearing white matter (NAWM) pathology in MS.
• The findings suggest Aze misincorporation into myelin proteins during myelinogenesis may be a primary driver of MS pathogenesis via a progressive unfolded protein response (UPR).
• This mouse model replicates MS NAWM pathology without requiring leukocyte infiltration.