A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy
Neurobiol Dis. 2021 Sep 9:105507. doi: 10.1016/j.nbd.2021.105507. Online ahead of print.ABSTRACTMutations in the lysosomal enzyme glucocerebrosidase (GCase, GBA1 gene) are the most common genetic risk factor for developing Parkinson's disease (PD). GCase metabolizes the glycosphingolipids glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph). Mutations in GBA1 reduce enzyme activity and the resulting accumulation of glycosphingolipids may contribute to the underlying pathology of PD, possibly via altering lysosomal function. While reduction of GCase activity exacerbates α-synuclein (α-syn) aggregation, it has not been determined that this effect is the result of altered glycosphingolipid levels and lysosome function or some other effect of altering GCase. The glycosphingolipid GlcCer is synthesized by a single enzyme, glucosylceramide synthase (GCS), and small molecule inhibitors (GCSi) reduce cellular glycosphingolipid levels. In the present studies, we utilize a preformed fibril (PFF) rodent primary neuron in vitro model of α-syn pathology to investigate the relationship between glycosphingolipid levels, α-syn pathology, and lysosomal function. In primary cultures, pharmacological inhibition of GCase and D409V GBA1 mutation enhanced accumulation of glycosphingolipids and insoluble phosphorylated α-syn. Administration of a novel small molecule GCSi, benzoxazole 1 (BZ1), significantly decreased glycosphingolipid concentrations in rodent primary neurons and reduced Î...
Source: Neurobiology of Disease - Category: Neurology Authors: Mali Cosden Sarah Jinn Lihang Yao Cheryl A Gretzula Monika Kandebo Dawn Toolan Nathan G Hatcher Lei Ma Wei Lemaire Gregory C Adam Christine Burlein Christina Minnick Rose Flick Marla L Watt James Mulhearn Mark Fraley Robert E Drolet Jacob N Marcus Sean M Source Type: research
More News: Biology | Brain | Genetics | Mali Health | Neurology | Parkinson's Disease | Pathology | Study