Abstract
p25α/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules. In multiple system atrophy (MSA), TPPP is suggested to relocate from the myelin sheath to the oligodendroglial cell body, before the formation of glial cytoplasmic inclusions (GCIs), the pathologic hallmark of MSA. However, much is left unknown about the re-distribution of TPPP in MSA. We generated new antibodies against the N- and C-terminus of TPPP, and analyzed control and MSA brains, including the brain of a familial MSA patient carrying homozygous mutations in the coenzyme Q2 gene (COQ2). In control brain tissues, TPPP was localized not only in the cytoplasmic component of the oligodendroglia including perinuclear cytoplasm and peripheral processes in the white matter, but also in the nucleus of a fraction (62.4%) of oligodendroglial cells. Immunoelectron microscopic analysis showed TPPP in the nucleus and mitochondrial membrane of normal oligodendroglia, while western blot also supported its nuclear and mitochondrial existence. In MSA, the prevalence of nuclear TPPP was 48.6% in the oligodendroglia lacking GCIs, whereas it was further decreased to 19.6% in the oligodendroglia with phosphorylated α-synuclein (pα-syn)-positive GCIs, both showing a significant decrease compared to controls (62.4%). In contrast, TPPP accumulated in the perinuclear cytoplasm where mitochondrial membrane (TOM20 and cytochrome C) and fission (DRP1) proteins were often immunoreactive. We conclude that in MSA-oligodendroglia, TPPP is reduced, not only in the peripheral cytoplasm, but also in the nucleus and relocated to the perinuclear cytoplasm.
Highlights
P25α/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules
We found that TPPP is expressed abundantly in the cytoplasm and processes including the myelin sheath as previously described
Whereas most previous reports emphasized that TPPP was expressed in the oligodendroglial cytoplasm and all oligodendroglial processes [7,8], two studies previously reported that TPPP is localized in the nucleus [10,20], consistent with the present data
Summary
P25α/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules. TPPP was localized in the cytoplasmic component of the oligodendroglia including perinuclear cytoplasm and peripheral processes in the white matter, and in the nucleus of a fraction (62.4%) of oligodendroglial cells. Previous pathological studies on human MSA brains showed that TPPP alters its distribution from the myelin sheath to the cell soma where it colocalizes with α-syn-containing GCIs [8,12]. In MSA, TPPP was lost from the oligodendroglial peripheral processes including myelin sheaths, and from the oligodendroglial nuclei, and accumulated in its cell body where increased immunoreactivity was seen for two mitochondrial membrane proteins (translocase of the mitochondrial outer membrane 20 [TOM20] and cytochrome C), and dynamin-related protein 1 (DRP1) that mediates mitochondrial fission. We propose the amount of nuclear TPPP is reduced in MSA and this may perturb normal, yet unknown nuclear functions
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