Objective: We investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies.

Background: Mutations in GBA, the gene encoding glucocerebrosidase, are associated with an enhanced risk of developing synucleinopathies such as Parkinson’s disease (PD). Recent studies have demonstrated that genetic variation in GBA can also impact the progression of PD. Patients harboring mutations in GBA present higher prevalence and severity of motor and non-motor symptoms. However, the precise mechanisms by which mutations in GBA increase PD risk and exacerbate its progression remain unclear.

Methods: Two murine models of synucleinopathy (Gba^D409V/D409V and PrP-A53T-SNCA) were treated with a brain-penetrant GCS inhibitor, GZ667161 for 6 to 9 months.

Results: As expected, treatment of Gba^D409V/D409V with the GCS inhibitor for 9 months reduced the levels glucosylceramide and glucosylsphingosine in the CNS. Most notably, this exposure to GZ667161 slowed the accumulation of hippocampal aggregates of α-synuclein, ubiquitin and tau, and improved the associated memory deficits. The effects of the GCS inhibitor were also studied in a mouse model overexpressing α-synuclein, PrP-A53T-SNCA, and harboring wild type alleles of GBA. Treatment of PrP-A53T-SNCA mice with GZ667161 for 6.5 months reduced membrane-associated α-synuclein in the CNS and ameliorated cognitive deficits.

Conclusions: Collectively, the data indicate that inhibition of GCS can modulate processing of α-synuclein and reduce various α-synuclein entities, thereby reducing the progression of synucleinopathies in mice with and without mutations in GBA. The present study provides supporting evidence for the clinical development of brain-penetrant GCS inhibitors in PD and other synucleinopathies.

« Back to 2016 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/inhibition-of-glucosylceramide-synthase-reduces-pathology-and-improves-cognition-in-synucleinopathy-murine-models/