visible protein aggregates, or inclusion bodies, within neural cells. The ubiquitin homologue, SUMO-1, has been identified in sub-domains of pathological inclusion bodies in several neurodegenerative diseases. Inclusion bodies are believed to be formed actively in a defensive response to soluble cytotoxic protein aggregates. We hypothesised that SUMO-1 may become associated with lysosomes in this response. Protein aggregation was induced in 1321N1 glioma cells by proteasome inhibition with MG132 or by transient transfection with Q74-EGFP. Fluorescence immunohistochemistry identified co-localisation of SUMO-1 and the lysosomal marker, cathepsin D, in both the transfected cells and MG132-treated cells, increasing over time at 24-96 hrs post-transfection/treatment. SUMO-1-positive lysosomes were also detected following MG132-treatment of 1321N1 cells expressing SUMO-1-GFP and stained with Lysotracker dye. SUMO-1 did not mark lysosomes in untransfected or sham treated cells. To determine if SUMO-1 also marks lysosomes in disease, we examined 5 cases of progressive supranuclear palsy (PSP), 5 cases of multiple system atrophy (MSA) and a rat Parkinson's disease model. Punctate co-localisation of cathepsin D and SUMO-1 was consistently associated with both the tau-positive PSP inclusions and the a-synuclein-positive MSA and rat PD model inclusions. A similar pattern was also found with the OLN-t40 oligodendrocyte model. These findings suggest a role for SUMO-1 in the autophagy-lysosome pathway linked to the response to protein aggregates.