Mutations in the glucocerebrosidase gene (GBA) confer a heightened risk of developing Parkinson's disease (PD) and other synucleinopathies, resulting in a lower age of onset and exacerbating disease progression. However, the precise mechanisms by which mutations in GBA increase PD risk and accelerate its progression remain unclear. Here, we investigated the merits of glucosylceramide synthase (GCS) inhibition as a potential treatment for synucleinopathies. Two murine models of synucleinopathy (a Gaucher-related synucleinopathy model, Gba D409V/D409V and a A53T-α-synuclein overexpressing model harboring wild-type alleles of GBA, A53T-SNCA mouse model) were exposed to a brain-penetrant GCS inhibitor, GZ667161. Treatment of Gba D409V/D409V mice with the GCS inhibitor reduced levels of glucosylceramide and glucosylsphingosine in the central nervous system (CNS), demonstrating target engagement. Remarkably, treatment with GZ667161 slowed the accumulation of hippocampal aggregates of α-synuclein, ubiquitin, and tau, and improved the associated memory deficits. Similarly, prolonged treatment of A53T-SNCA mice with GZ667161 reduced membrane-associated α-synuclein in the CNS and ameliorated cognitive deficits. The data support the contention that prolonged antagonism of GCS in the CNS can affect α-synuclein processing and improve behavioral outcomes. Hence, inhibition of GCS represents a diseasemodifying therapeutic strategy for GBA-related synucleinopathies and conceivably for certain forms of sporadic disease.Parkinson's disease | GBA mutations | glucosylceramide synthase | Gaucher disease | Lewy body dementia
Proteins of the regulators of G protein signaling (RGS) family modulate the duration of intracellular signaling by stimulating the GTPase activity of G protein ␣ subunits. It has been established that the ninth member of the RGS family (RGS9) participates in accelerating the GTPase activity of the photoreceptor-specific G protein, transducin. This process is essential for timely inactivation of the phototransduction cascade during the recovery from a photoresponse. Here we report that functionally active RGS9 from vertebrate photoreceptors exists as a tight complex with the long splice variant of the G protein  subunit (G 5L ). RGS9 and G 5L also form a complex when coexpressed in cell culture. Our data are consistent with the recent observation that several RGS proteins, including RGS9, contain G protein ␥-subunit like domain that can mediate their association with G 5 ( Heterotrimeric G proteins act as molecular switches that relay excitation from activated receptors to effector molecules, such as enzymes or ion channels. A G protein becomes activated upon the receptor-stimulated binding of GTP to its ␣ subunit and continues to modulate the activity of the effector until bound GTP is hydrolyzed (reviewed in refs. 1 and 2). In many signaling pathways, the duration of the signal under physiological conditions is much shorter than would be predicted from the intrinsic rate of ␣ subunits of G proteins (G ␣ ) GTPase activity. This is because GTPase activities of many G ␣ s are dramatically accelerated by RGS (regulators of G protein signaling) proteins or by the G protein effectors (reviewed in refs. 3-6). The phototransduction cascade of vertebrate photoreceptors represents one of the most sophisticated examples of such regulation where the GTPase activity of the G protein, transducin, is substantially enhanced by the cooperative action of RGS9 and the ␥ subunit of the effector of transducin, cGMP phosphodiesterase (PDE ␥ ) (7-10). The role of RGS9 is to provide transducin with the RGS homology domain, which acts catalytically in stimulating the rate of transducin GTPase. PDE ␥ itself does not activate transducin GTPase but it enhances the catalytic action of RGS9. The degree of this potentiation observed in physiologically intact photoreceptors is Ϸ7-fold (10). We believe that this ability of PDE ␥ to potentiate RGS9 action is essential for photoreceptor function. When a rod photoreceptor is hit by photon of light it has to perform two tasks. First, it has to transmit the signal from excited rhodopsin to PDE with high efficiency. Second, it has to inactivate all activated proteins in the cascade, including transducin, within a fraction of 1 s. If transducin is allowed to be discharged by RGS9 before it forms a complex with PDE, then some transducin molecules would never activate PDE and signal amplification would be diminished. Therefore, making the GTPase activation contingent on transducin association with PDE ␥ ensures both high efficiency of signal transmission between transducin and PDE and timel...
Metachromatic leukodystrophy (MLD) is a rare, genetic lysosomal storage disorder caused by the deficiency of arylsulfatase A enzyme, which results in the accumulation of sulfatide in the lysosomes of the tissues of central and peripheral nervous systems, leading to progressive demyelination and neurodegeneration. Currently there is no cure for this disease, and the only approved therapy, hematopoietic stem cell transplant, has limitations. We proposed substrate reduction therapy (SRT) as a novel approach to treat this disease, by inhibiting ceramide galactosyltransferase enzyme (UGT8). This resulted in the identification of a thienopyridine scaffold as a starting point to initiate medicinal chemistry. Further optimization of hit compound 1 resulted in the identification of brain penetrable, orally bioavailable compound 19, which showed efficacy in the in vivo pharmacodynamic models, indicating the potential to treat MLD with UGT8 inhibitors.
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