Insertion of proteolipid protein into oligodendrocyte mitochondria regulates extracellular pH and adenosine triphosphate. Issue 3 (31st December 2013)

• Record Type: Journal Article
• Authors: Appikatla, Sunita; Bessert, Denise; Lee, Icksoo; Hüttemann, Maik; Mullins, Chadwick; Somayajulu‐Nitu, Mallika; Yao, Fayi; Skoff, Robert P.
• Is Part Of: Glia. Volume 62:Issue 3(2014:Mar.)
• Page Start: 356
• Page End: 373
• Publication Date: 2013-12-31
• Subjects: Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.22591
• Languages: English
• ISSNs: 0894-1491

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Proteolipid protein (PLP) and DM20, the most abundant myelin proteins, are coded by the human <italic>PLP1</italic> and non‐human <italic>Plp1</italic> PLP gene. Mutations in the <italic>PLP1</italic> gene cause Pelizaeus–Merzbacher disease (PMD) with duplications of the native <italic>PLP1</italic> gene accounting for 70% of <italic>PLP1</italic> mutations. Humans with <italic>PLP1</italic> duplications and mice with extra <italic>Plp1</italic> copies have extensive neuronal degeneration. The mechanism that causes neuronal degeneration is unknown. We show that native PLP traffics to mitochondria when the gene is duplicated in mice and in humans. This report is the first demonstration of a specific cellular defect in brains of PMD patients; it validates rodent models as ideal models to study PMD. Insertion of nuclear‐encoded mitochondrial proteins requires specific import pathways; we show that specific cysteine motifs, part of the Mia40/Erv1 mitochondrial import pathway, are present in PLP and are required for its insertion into mitochondria. Insertion of native PLP into mitochondria of transfected cells acidifies media, partially due to increased lactate; it also increases adenosine triphosphate (ATP) in the media. The same abnormalities are found in the extracellular space of mouse brains with extra copies of <italic>Plp1</italic>. These physiological abnormalities are preventable by mutations in PLP cysteine motifs, a hallmark of the Mia40/Erv1 pathway. Increased extracellular ATP and acidosis lead to neuronal degeneration. Our findings may be the mechanism by which microglia are activated and proinflammatory molecules are upregulated in <italic>Plp1</italic> transgenic mice (Tatar et al. (2010) ASN Neuro 2:art:e00043). Manipulation of this metabolic pathway may restore normal metabolism and provide therapy for PMD patients. GLIA 2014;62:356–373</p> </abstract>