title: Involvement of macroautophagy in multiple system atrophy and protein aggregate formation in oligodendrocytes.
abstract: α-Synuclein-containing glial cytoplasmic inclusions (GCIs) originating in oligodendrocytes are the characteristic hallmark for neuropathological diagnosis of multiple system atrophy (MSA). α-Synuclein can be degraded either by the proteasomal machinery or by autophagy, a lysosomal pathway which involves the formation of autophagosomes. The autophagosome takes up polyubiquitinated proteins via the autophagosomal protein LC3 and the ubiquitin binding protein p62. In the present study, neuropathological examination of seven MSA cases revealed that LC3-immunoreactivity is found to be associated with α-synuclein-positive GCIs. These are also prominently stained by antibodies against p62 and ubiquitin, indicating that the autophagic pathway is upregulated during pathogenesis, which might be due to a persistent downregulation of proteasomal activity. To further address this question in a cellular context, we have investigated whether proteasomal inhibition in cultured rat brain oligodendrocytes promotes the recruitment of LC3 and p62 to protein aggregates. The data show that the autophagic marker LC3-II is upregulated and LC3 is recruited to the growing protein aggregates in cultured oligodendrocytes when the proteasome is impaired. However, aggregated proteins remain in the oligodendroglial cytoplasm and cannot be cleared efficiently. In conclusion, autophagy and the ubiquitin proteasome system are closely connected, and the presence of LC3-positive vesicles in GCIs indicates that macroautophagy participates in MSA pathogenesis.
authors.affiliation: Department of Biology, Molecular Neurobiology, University of Oldenburg, POB 2503, 26111, Oldenburg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schwarz
authors.forename: Olaf
authors.initials: O
authors.lastname: Goldbaum
authors.forename: Markus
authors.initials: M
authors.lastname: Bergmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Probst-Cousin
authors.forename: Christiane
authors.initials: C
authors.lastname: Richter-Landsberg
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: C497604:SNCA protein, human; C497606:Snca protein, rat; D051844:alpha-Synuclein