title: SUMO-1 is associated with a subset of lysosomes in glial protein aggregate diseases.
abstract: Oligodendroglial inclusion bodies characterize a subset of neurodegenerative diseases. Multiple system atrophy (MSA) is characterized by α-synuclein glial cytoplasmic inclusions and progressive supranuclear palsy (PSP) is associated with glial tau inclusions. The ubiquitin homologue, SUMO-1, has been identified in inclusion bodies in MSA, located in discrete sub-domains in α-synuclein-positive inclusions. We investigated SUMO-1 associated with oligodendroglial inclusion bodies in brain tissue from MSA and PSP and in glial cell models. We examined MSA and PSP cases and compared to age-matched normal controls. Fluorescence immunohistochemistry revealed frequent SUMO-1 sub-domains within and surrounding inclusions bodies in both diseases and showed punctate co-localization of SUMO-1 and the lysosomal marker, cathepsin D, in affected brain regions. Cell counting data revealed that 70-75 % of lysosomes in inclusion body-positive oligodendrocytes were SUMO-1-positive consistently across MSA and PSP cases, compared to 20 % in neighbouring inclusion body negative oligodendrocytes and 10 % in normal brain tissue. Hsp90 co-localized with some SUMO-1 puncta. We examined the SUMO-1 status of lysosomes in 1321N1 human glioma cells over-expressing α-synuclein and in immortalized rat oligodendrocyte cells over-expressing the four repeat form of tau following treatment with the proteasome inhibitor, MG132. We also transfected 1321N1 cells with the inherently aggregation-prone huntingtin exon 1 mutant, HttQ74-GFP. Each cell model showed the association of SUMO-1-positive lysosomes around focal cytoplasmic accumulations of α-synuclein, tau or HttQ74-GFP, respectively. Association of SUMO-1 with lysosomes was also detected in glial cells bearing α-synuclein aggregates in a rotenone-lesioned rat model. SUMO-1 labelling of lysosomes showed a major increase between 24 and 48 h post-incubation of 1321N1 cells with MG132 resulting in an increase in a 90 kDa SUMO-1-positive band that was immunopositive for Hsp90 and immunoprecipitated with an anti-SUMO-1 antibody. That SUMO-1 co-localizes with a subset of lysosomes in neurodegenerative diseases with glial protein aggregates and in glial cell culture models of protein aggregation suggests a role for SUMO-1 in lysosome function.
authors.affiliation: School of Medical Science, Griffith Health Institute, Griffith University, Gold Coast Campus, Gold Coast, QLD 4222, Australia.
authors.forename: Mathew B
authors.initials: MB
authors.lastname: Wong
authors.forename: Jacob
authors.initials: J
authors.lastname: Goodwin
authors.forename: Anwar
authors.initials: A
authors.lastname: Norazit
authors.forename: Adrian C B
authors.initials: AC
authors.lastname: Meedeniya
authors.forename: Christiane
authors.initials: C
authors.lastname: Richter-Landsberg
authors.forename: Wei Ping
authors.initials: WP
authors.lastname: Gai
authors.forename: Dean L
authors.initials: DL
authors.lastname: Pountney
mesh_terms: D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D025842:SUMO-1 Protein / Q000378:metabolism*
chemical_list: D025842:SUMO-1 Protein