Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

Abstract

Abstractp25α/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.

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

“…In addition, both TPPP/p25 [15] and SYN [60] were detected in the cerebrospinal fluid of human patients. Extracellular transmission of these proteins, therefore, is a plausible explanation for the development of pathological inclusions in the case of Parkinson's disease and multiple system atrophy [16,61,62].…”

“…Targeting by competitors/foldamers should impede/destruct the small soluble assemblies, the fatal species in the development of synucleinopathies. The pathological complex has been suggested functioning as an initiator in the etiology of Parkinson's disease and multiple system atrophy [16][17][18]61,62]. We explored the challenges associated with targeting chameleon proteins using the TPPP/p25-SYN complex as a case study.…”

Neuropathology of multiple system atrophy: New thoughts about pathogenesis

“…In the rostral pons of MSA patients, significant changes in the expression of 254 genes were found, some similar to those in substantia nigra (SN) of patients with PD and others related to oligodendroglial function . Functionally impaired variants of parahydroxybenzoate‐polyprenyltransferase (COQ2) as a risk factor for MSA found in a Japanese family carrying homozygous mutations in the coenzyme Q2 gene (COQ2) have not been confirmed by others, and no association of glucosidase‐β‐acid (GBA) mutations and MSA, and no c9orf72 expansions have been found . An autosomal dominant inheritance within a German MSA family was reported .…”

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

“…The assembly of the unstructured SYN and TPPP/ p25 appears to be pathogenic leading to the etiology of synucleinopathies [99,103,104,107]. Indeed, their coenrichment and co-localization has been detected in both neurons and OLGs in the cases of PD and MSA, respectively, [99,103,104,107] (Fig.…”

“…TPPP/p25 and SYN co-localize and are co-enriched in both neurons and OLGs in PD and MSA, respectively (Fig. 2) [99,[103][104][105][106][107][108]. In OLG cell models of MSA that involve TPPP/p25 and SYN overexpression, TPPP/p25-induced SYN aggregation was detected [79,109].…”