| First Author | Burbulla LF | Year | 2019 |
| Journal | Sci Transl Med | Volume | 11 |
| Issue | 514 | PubMed ID | 31619543 |
| Mgi Jnum | J:279956 | Mgi Id | MGI:6368056 |
| Doi | 10.1126/scitranslmed.aau6870 | Citation | Burbulla LF, et al. (2019) A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease. Sci Transl Med 11(514) |
| abstractText | Mutations in the GBA1 gene encoding the lysosomal enzyme beta-glucocerebrosidase (GCase) represent the most common risk factor for Parkinson's disease (PD). GCase has been identified as a potential therapeutic target for PD and current efforts are focused on chemical chaperones to translocate mutant GCase into lysosomes. However, for several GBA1-linked forms of PD and PD associated with mutations in LRRK2, DJ-1, and PARKIN, activating wild-type GCase represents an alternative approach. We developed a new small-molecule modulator of GCase called S-181 that increased wild-type GCase activity in iPSC-derived dopaminergic neurons from sporadic PD patients, as well as patients carrying the 84GG mutation in GBA1, or mutations in LRRK2, DJ-1, or PARKIN who had decreased GCase activity. S-181 treatment of these PD iPSC-derived dopaminergic neurons partially restored lysosomal function and lowered accumulation of oxidized dopamine, glucosylceramide and alpha-synuclein. Moreover, S-181 treatment of mice heterozygous for the D409V GBA1 mutation (Gba1(D409V/+) ) resulted in activation of wild-type GCase and consequent reduction of GCase lipid substrates and alpha-synuclein in mouse brain tissue. Our findings point to activation of wild-type GCase by small-molecule modulators as a potential therapeutic approach for treating familial and sporadic forms of PD that exhibit decreased GCase activity. |
