Gibson Lab

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Laboratory for Mitochondrial Biology and Metabolic Dysfunction in Neurodegeneration

The elderly are at a greater risk for many neurodegenerative diseases. The most common of these age-related diseases are Alzheimer’s, Parkinson’s and Huntington’s diseases. The goals of our laboratory are to discover the underlying cause of age-related neurodegenerative diseases and to develop effective therapies. The brain is very dependent on oxygen and glucose (sugar). Our research shows that many age-related diseases and stroke may share similar fundamental mechanisms of damage, i.e., a reduced ability to use glucose and oxygen, which either causes the disease(s) or is a critical clinically relevant change. We are trying to determine why this reduction occurs and its consequences for brain function. 

Our studies show that oxidative stress induced post-translational modification of key glucose metabolic enzymes is likely to contribute to the reduced glucose utilization. Abnormalities in the use of glucose and oxygen cause dysregulation of calcium and the production of excess free radicals, which in turn, may lead to the brain dysfunction. Thus, reversing diminished use of glucose, preventing the free radical damage, or a change in calcium with specific drugs should protect the brain. Cells from patients, genetically modified cells and animal models are being used to test these possibilities and to evaluate the effectiveness of drugs.

Inhibition of KGDHC (CESP) reduces succinylation in cultured neurons. KGDHC is responsible for succinylation of multiple proteins.

Inhibition of KGDHC (CESP) reduces succinylation in cultured neurons. KGDHC is responsible for succinylation of multiple proteins. N2a cells were incubated with or without an inhibitor of KGDHC and proteins were isolated were assessed for succinylation.

Method for transfecting NADH sensors in N2a cells

Method for transfecting NADH sensors in N2a cells
Cell culture: N2a cells were placed on the Delta TPG dishes at a seeding density of 4 × 105 cells/dish and cultured for 3 days.
NADH sensor and pH sensor transfection: N2a cells were transfected with NADH sensors (2 mg) and pH sensors (2 mg) with Lipofectamine 2000 transfect reagent for 48 hr at 37°C.
Fluorescent signals detection: After 48 hr of transfection, the fluorescent signals were acquired with confocal microscopy at excitation of 488 nm.
NADH level determination: NADH level were calculated by normalizing signal of pH sensor with the signal of NADH sensor.

Featured Research Projects

RESEARCH PROJECT: 
In Progress
Thiamine (vitamin B1) dependent processes are reduced in Alzheimer’s disease. Thiamine deficiency mimics many aspects of Alzheimer’s disease including the reduced glucose metabolism and exaggeration of the plaque and tangle pathology.
RESEARCH PROJECT: 
In Progress
We postulate that critical enzymes are modified post-translationally in Alzheimer’s disease. The focus is on the key mitochondrial enzyme alpha-ketoglutarate dehydrogenase complex (KGDHC).
RESEARCH PROJECT: 
In Progress
Reducing the enzyme KGHDC has widespread consequences on cell and brain function. We postulate this is because it is responsible for post-translation modification of thousands of proteins by succinylation.
RESEARCH PROJECT: 
In Progress
Alzheimer’s disease related changes in releasable internal calcium stores as well as in mitochondrial function have been suggested from animal studies and cultured cells from Alzheimer’s disease patients such as fibroblasts, and make good therapeutic targets.
RESEARCH PROJECT: 
In Progress

The investigators on the program project have two mechanisms for resource sharing.

RESEARCH PROJECT: 
In Progress

Mitochondrial dysfunction and oxidative stress are consistent features of multiple neurodegenerative diseases including Alzheimer’s disease (AD).

RESEARCH PROJECT: 
In Progress

Diminished brain metabolism and oxidative stress are characteristic features of Alzheimer's disease (AD). The mechanisms underlying these changes are as yet poorly defined.

RESEARCH PROJECT: 
In Progress

Thiamine (vitamin B1) deficiency (TD) produces a mild, chronic impairment of oxidative metabolism that models the diminished metabolism and reduced activities of the thiamine-dependent mitochondrial enzymes that occur in brain in several com

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Gary E. Gibson, Ph.D.

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