Inhibiting the Cytotoxic Effect of Tubulin Polymerization-Promoting Protein (TPPP/p25α) Induced α-synuclein Aggregates Via 20S Proteasome Enhancement

Abstract ID 129750 Poster Board 095 Multiple System Atrophy (MSA) belongs to a subset of Neurodegenerative Diseases (NDs) known as synucleinopathies, which includes Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). The accumulation of aggregates of α-synuclein proteins characterizes these NDs, albeit in different strains. In MSA, the α-synuclein aggregates called Glial Cytoplasmic Inclusions (GCIs) accumulate in oligodendrocytes. In addition, GCIs also contain inclusions of Tubulin Polymerization-Promoting Protein (TPPP/p25α). p25α is expressed in mature oligodendrocytes and is vital for the stabilization and reorganization of myelin. It is believed that p25α migrates from the nucleus into the cytosol, where it co-aggregates with α-synuclein to form GCI, disrupting cell processes and ultimately leading to cell death. There is no efficient MSA therapy to date. One novel disease-modifying approach is to inhibit the formation of α-synuclein aggregate. This report shows that 20S proteasome activators can enhance the proteolysis of p25α, inhibiting its co-aggregation with α-synuclein and restoring proteasome impairment and cell viability. The authors gratefully acknowledge financial support from the National Institutes of Health, National Institute of Aging, R21 AG061306 (JJT).