OGA

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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 [...]

December 1st, 2020|Tags: , , |

MK-8719, a Novel and Selective O-GlcNAcase Inhibitor That Reduces the Formation of Pathological Tau and Ameliorates Neurodegeneration in a Mouse Model of Tauopathy

Deposition of hyperphosphorylated and aggregated tau protein in the central nervous system is characteristic of Alzheimer disease and other tauopathies. Tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and O-GlcNAcylation of tau has been shown to influence tau phosphorylation and aggregation. Inhibition of O-GlcNAcase (OGA), the enzyme that removes O-GlcNAc moieties, is a novel strategy [...]

July 1st, 2020|Tags: , , , , , , |

The Discovery and Characterization of [18F]MK‐8553, a Novel PET Tracer for Imaging O‐GlcNAcase (OGA)

[18F]MK-8553 is a high affinity, selective OGA inhibitor with properties suitable for imaging OGA and determining central enzyme occupancy in both preclinical and clinical studies. Currently [18F]MK‐8553 is being utilized in humans as a PET tracer to assess CNS target engagement to select a dose for clinical proof of concept trials with a small molecule [...]

July 14th, 2016|Tags: , , , |

Alectos Therapeutics Announces FDA Orphan Drug Designation for MK-8719: An Investigational Small-molecule OGA Inhibitor for Treatment of Progressive Supranuclear Palsy

Advances Novel Tau-directed Strategy for Treating Neurodegenerative Disease Phase 1 Clinical Trial Completed Vancouver, British Columbia (April 20, 2016) – Alectos Therapeutics Inc. today announced that the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to OGA inhibitor MK-8719 for the treatment of progressive supranuclear palsy (PSP). Alectos also announced completion of [...]

April 20th, 2016|Tags: , , , , , |

Preclinical Data Disclosed for Tau PET Tracer MK-6240: A Potential Clinical Biomarker for OGA Inhibitor MK-8719

Apr 18, 2016 – Alectos Therapeutics partner Merck, known as MSD outside the U.S. and Canada, today disclosed preclinical data for potential clinical biomarker [18F]-MK-6240, a highly selective and specific tau PET tracer useful as an imaging agent for quantification of neurofibrillary tangles (NFTs). A pathological hallmark of Alzheimer's disease, as well as several other neurodegenerative [...]

April 18th, 2016|Tags: , , , , , , |

O-GlcNAc modification blocks the aggregation and toxicity of the protein α-synuclein associated with Parkinson’s disease

Several aggregation-prone proteins associated with neurodegenerative diseases can be modified by O-linked N-acetyl-glucosamine (O-GlcNAc) in vivo. One of these proteins, α-synuclein, is a toxic aggregating protein associated with synucleinopathies, including Parkinson's disease. However, the effect of O-GlcNAcylation on α-synuclein is not clear. Here, we use synthetic protein chemistry to generate both unmodified α-synuclein and α-synuclein [...]

October 12th, 2015|Tags: , , |

Alectos Therapeutics Announces Achievement of Phase I Clinical Milestone in Merck Alzheimer’s Collaboration

Vancouver, British Columbia (December 12, 2014) – Alectos Therapeutics Inc. today announced the initiation of a Phase I clinical trial in its collaboration with Merck, known as MSD outside the U.S. and Canada, to identify and develop compounds that modulate O-linked N-acetylglucosaminidase (OGA), an enzyme that is believed to be involved in the development of [...]

December 12th, 2014|Tags: , , , |

Alectos Announces Preclinical Results in TAPP Mouse Model of Alzheimer’s Disease

Oct 26, 2014 – Alectos today announced publication of preclinical studies showing that pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in the TAPP mouse model of Alzheimer’s disease. For details, see: Yuzwa, S.A. et al. Mol Neurodegener 9:42 (2014).

October 26th, 2014|Tags: , , , , , , , |

Pharmacological inhibition of O-GlcNAcase (OGA) prevents cognitive decline and amyloid plaque formation in bigenic tau/APP mutant mice

BACKGROUND: Amyloid plaques and neurofibrillary tangles (NFTs) are the defining pathological hallmarks of Alzheimer's disease (AD). Increasing the quantity of the O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of nuclear and cytoplasmic proteins slows neurodegeneration and blocks the formation of NFTs in a tauopathy mouse model. It remains unknown, however, if O-GlcNAc can influence the formation of [...]

October 26th, 2014|Tags: , , , , , , , |

The emerging link between O-GlcNAc and Alzheimer disease

Regional glucose hypometabolism is a defining feature of Alzheimer disease (AD). One emerging link between glucose hypometabolism and progression of AD is the nutrient-responsive post-translational O-GlcNAcylation of nucleocytoplasmic proteins. O-GlcNAc is abundant in neurons and occurs on both tau and amyloid precursor protein. Increased brain O-GlcNAcylation protects against tau and amyloid-β peptide toxicity. Decreased O-GlcNAcylation [...]

October 21st, 2014|Tags: , , , , , , , , , , |