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O4‐03‐01: Autophagic‐lysosomal dysfunction in glucocerebrosidase‐associated dementia with lewy bodies

2011; Wiley; Volume: 7; Issue: 4S_Part_20 Linguagem: Inglês

10.1016/j.jalz.2011.05.1980

1552-5279

Wen H. Yu, Li Liu, Chan Robin, Mathieu Herman, Helen Y. Figueroa, Markus R. Wenk, Karen Duff,

Autism Spectrum Disorder Research

Glucocerebrosidase (GBA) is a lysosomal-residentenzyme responsible for the degradation of glucocerebrosides. Mutations in the GBA gene attenuate GBA function, with complex heterozygote and homozygote mutant carriers having no GBA activity which is seen in Gaucher's disease, the most common lysosomal storage disorder. Genetic analyses from multiple research groups have identified that GBA mutations are the most significant known genetic risk factor for Parkinson's disease and Parkinsonism. Carriers of a mutant form of GBA are at five times greater risk of developing Parkinsonism than the non-affected population. Moreover, there appears to be an increase in alpha-synuclein deposition in the regions associated with cognition like the hippocampus and entorhinal cortex, suggesting these regions may be vulnerable to GBA dysfunction. This study will examine the effect of GBA dysfunction on the autophagic-lysosomal system (A-LS) and synucleinopathy to identify if protein quality control is disrupted in areas that have high constitutive A-LS activity and are associated with Dementia with Lewy bodies (DLB). In cell models, GBA expression and activity was inhibited by genetic and pharmacological methods to see if protein and lipid degradation by A-LS was disrupted, and whether this led to proteinopathy, in particular, alpha-synuclein aggregation. Immunofluorescence and Western blotting detection of alpha-synuclein species and A-LS constituents was performed, and lipids were measured by mass spectroscopy. In whole animal models, GBA activity was inhibited to identify regional differences in protein aggregates and polyubiquitinated deposits. Addition of conduritol beta-epoxide (a specific glucocerebrosidase inhibitor) or RNAi specifically targeting GBA inhibited GBA activity resulted in the retention of autophagic vacuoles and an increasein alpha-synuclein aggregates and oligomers. Moreover, there were indications of protein quality control stress, as we observed increased ubiquitination and aggresome (p62) markers. In animal brains, we examined if autophagic and lysosomal processing were disrupted as a consequence of GBA inactivity and observed increased protein aggregates, lipid deposits and ubiquitinated proteins. Glucocerebrosidase dysfunction affects the autophagic-lysosomal system, particularly in regions associated with constitutively high A-LS activity resulting in reduced protein and lipid turnover. In these regions, it is likely to promote synucleinopathy and the progression of Parkinsonian neuropathology.