O-GlcNAcylation regulates dopamine neuron function, survival and degeneration in Parkinson disease

The dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson???s disease and prematurely degenerate in the course of disease progression, while the discovery of new therapeutic interventions has been disappointingly unsuccessful. Here, we show that O-GlcNAcylation, an essential post-translational modification in various types of cells, is critical for the physiological function and survival of dopamine neurons. Bidirectional modulation of O-GlcNAcylation importantly regulates dopamine neurons at the molecular, synaptic, cellular, and behavioural levels. Remarkably, genetic and pharmacological upregulation of O-GlcNAcylation mitigates neurodegeneration, synaptic impairments, and motor deficits in an animal model of Parkinson???s disease. These findings provide insights into the functional importance of O-GlcNAcylation in the dopamine system, which may be utilized to protect dopamine neurons against Parkinson???s disease pathology

The critical role of O-GlcNAcylation in dopamine neuron function, survival, and degeneration in health and Parkinson???s disease

Dopamine system in the midbrain is important for volitional movement, action selection, and reward-related learning. Even though dopamine system mediates versatile functions, it contains only a small set of neurons in the midbrain. Moreover, these dopamine neurons are highly susceptible to Parkinson???s disease (PD) and degenerate during disease progression. Here, we reveal that O-GlcNAcylation, an important post-translational modification in cells, is essential for survival and function of dopamine neurons. Modulation of O-GlcNAc level critically regulates dopamine neurons at molecular, synaptic, cellular, and behavioral levels. Notably, up-regulation of O-GlcNAcylation in dopamine neurons alleviates neurodegeneration, synaptic impairments, and motor deficits in an animal model of PD. These findings suggest the importance of O-GlcNAcylation in the dopamine system and may provide new therapeutic approach to protect dopamine neurons against PD pathology

O-GlcNAcylation governs functions, survival, and degeneration of dopamine neurons in health and Parkinson???s disease

Dopamine system in the midbrain is essential for volitional movement, action selection, and reward-related learning. Despite its versatile roles, it contains only a small set of neurons in the brainstem. These dopamine neurons are especially susceptible to Parkinson???s disease and prematurely degenerate in the course of disease progression, while the discovery of new therapeutic intervention has been disappointingly unsuccessful. Here, we show that O-GlcNAcylation, an essential post-translational modification in various types of cells, is critical for the physiological function and survival of dopamine neurons. Bi-directional modulation of O-GlcNAcylation importantly regulates dopamine neurons at the molecular, synaptic, cellular, and behavioral levels. Remarkably, genetic and pharmacological up-regulation of O-GlcNAcylation mitigates neurodegeneration, synaptic impairments, and motor deficits in an animal model of Parkinson???s disease. These findings provide insights into the functional importance of O-GlcNAcylation in the dopamine system, which may be utilized to protect dopamine neurons against Parkinson???s disease pathology

A Series of Novel Terpyridine-Skeleton Molecule Derivants Inhibit Tumor Growth and Metastasis by Targeting Topoisomerases

A series of novel terpyridine-skeleton molecules containing conformational rigidity, 14 containing benzo­[4,5]­furo­[3,2-<i>b</i>]­pyridine core and 15 comprising chromeno­[4,3-<i>b</i>]­pyridine core, were synthesized, and their biological activities were evaluated. 3-(4-Phenylbenzo­[4,5]­furo­[3,2-<i>b</i>]­pyridin-2-yl)­phenol (<b>8</b>) was determined to be a nonintercalative topo I and II dual catalytic inhibitor and 3-(4-phenylchromeno­[4,3-<i>b</i>]­pyridine-2-yl)­phenol (<b>22</b>) was determined to be a nonintercalative topo IIα specific catalytic inhibitor by various assays. These two catalytic inhibitors induced apoptosis in addition to G1 arrest in T47D human breast cancer cells with much less DNA toxicity than etoposide. Compounds <b>8</b> and <b>22</b> significantly inhibited tumor growth in HCT15 subcutaneously implanted xenografted mice. The modification of compounds <b>8</b> and <b>22</b> with the introduction of a methoxy instead of a hydroxy group enhanced endogenous topo inhibitory activity, metabolic stability in diverse types of liver microsomes and improved pharmacokinetic parameters in rat plasma such as augmentation of bioavailability (41.3% and 33.2% for 2-(3-methoxyphenyl)-4-phenyl­benzofuro­[3,2-<i>b</i>]­pyridine (<b>8-M</b>) and 3-(4-phenyl­chromeno­[4,3-<i>b</i>]­pyridine-2-yl)­methoxybenzene (<b>22-M</b>), respectively)