Publications

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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: , , , , , , |

Discovery of MK-8719, A Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies

Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) [...]

September 10th, 2019|Tags: , , , , , |

Cytosolic Glucosylceramide Regulates Endolysosomal Function in Niemann-Pick type C Disease

Niemann-Pick type C disease (NPCD) is a neurodegenerative disease associated with increases in cellular cholesterol and glycolipids and most commonly caused by defective NPC1, a late endosomal protein. Using ratiometric probes we find that NPCD cells show increased endolysosomal pH. In addition U18666A, an inhibitor of NPC1, was found to increase endolysosomal pH, and the [...]

March 12th, 2019|Tags: , , |

N-Butyldeoxynojirimycin Delays Motor Deficits, Cerebellar Microgliosis, and Purkinje Cell Loss in a Mouse Model of Mucolipidosis type IV

Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive intellectual disability, motor impairment, and premature death. There is currently no cure or corrective treatment. The disease results from mutations in the gene encoding mucolipin-1, a transient receptor potential channel believed to play a key role in lysosomal calcium egress. Loss of mucolipin-1 and [...]

June 10th, 2017|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: , , , |

Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice

The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, [...]

June 1st, 2016|Tags: , , |

Discovery of [18F]-MK-6240: A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs)

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate discovery of new disease modifying therapeutics targeting tau pathology. Herein we present the [...]

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: , , |

Structures of lactate dehydrogenase A (LDHA) in apo, ternary and inhibitor-bound forms

Lactate dehydrogenase (LDH) is an essential metabolic enzyme that catalyzes the interconversion of pyruvate and lactate using NADH/NAD(+) as a co-substrate. Many cancer cells exhibit a glycolytic phenotype known as the Warburg effect, in which elevated LDH levels enhance the conversion of glucose to lactate, making LDH an attractive therapeutic target for oncology. Two known [...]

January 23rd, 2015|Tags: , , , |