Wong_2016_Mov.Disord_31_1610

Lysosomal dysfunction has been implicated in multiple diseases, including lysosomal storage disorders such as Gaucher's disease, in which loss-of-function mutations in the GBA1 gene encoding the lysosomal hydrolase beta-glucocerebrosidase result in lipid substrate accumulation. In Parkinson's disease, alpha-synuclein accumulates in Lewy bodies and neurites contributing to neuronal death. Previous clinical and genetic evidence has demonstrated an important link between Parkinson's and Gaucher's disease, as GBA1 mutations and variants increase the risk of Parkinson's and Parkinson's patients exhibit decreased beta-glucocerebrosidase activity. Using human midbrain neuron cultures, we have found that loss of beta-glucocerebrosidase activity promotes alpha-synuclein accumulation and toxicity, whereas alpha-synuclein accumulation further contributes to decreased lysosomal beta-glucocerebrosidase activity by disrupting beta-glucocerebrosidase trafficking to lysosomes. Moreover, alpha-synuclein accumulation disrupts trafficking of additional lysosomal hydrolases, further contributing to lysosomal dysfunction and neuronal dyshomeostasis. Importantly, promoting beta-glucocerebrosidase activity reduces alpha-synuclein accumulation and rescues lysosomal and neuronal dysfunction, suggesting that beta-glucocerebrosidase may be an important therapeutic target for advancing drug discovery in synucleinopathies including Parkinson's disease. (c) 2016 International Parkinson and Movement Disorder Society.