A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson’s disease

Abstract

Mutations in the GBA1 gene encoding the lysosomal enzyme β-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 α-synuclein. Moreover, S-181 treatment of mice heterozygous for the D409V GBA1 mutation (Gba1D409V/+) resulted in activation of wild-type GCase and consequent reduction of GCase lipid substrates and α-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.

LRRK2 mediates tubulation and vesicle sorting from membrane damaged lysosomes

“…An accumulation of lysosomal damage with age in kidneys, which normally express high levels of LRRK2, has been documented in knockout mice (13), (14), (15). Pathogenic LRRK2 mutations affect lysosomal structure and function in cultured astrocytes (16) and other cell types (17), (18), (19), (20). However, the mechanistic basis by which LRRK2 affects lysosome function is unclear.…”

Botanical Drug Puerarin Promotes Neuronal Survival and Neurite Outgrowth against MPTP/MPP+-Induced Toxicity via Progesterone Receptor Signaling

“…Early diagnosis and early intervention are equally important to maintain the life quality of PD patients [ 31 , 32 ]. While the efficacy of the existing clinical drugs is controversial, natural product flavonoids hold promise for halting the progression of the disease and restoring the neuronal functions in PD patients [ 17 ].…”

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

“…Using high-throughput screening, two GBA1 chaperone compounds, NCGC607 and NCGC758, have been tested in iPSC-derived dopaminergic neurons from PD patients and induced improved GCase activity as well as decreased levels of α-syn and GCase substrates [355,356]. In the same line of evidence, using a Gaucher's disease mice model, administration of another GCase modulator S-181 that stabilizes wild-type GCase protein was sufficient to decrease lipid substrates and α-syn in mice brains [357]. Targeting another lysosomal hydrolase, direct overexpression of Cathepsin D gene into mammalian cells and human α-syn-transgenic C. elegans induced neuroprotective effects against α-syn aggregation and toxicity [358].…”