DNA polymerase β decrement triggers death of olfactory bulb cells and impairs olfaction in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) involves the progressive degeneration of neurons critical for learning and memory. In addition, patients with AD typically exhibit impaired olfaction associated with neuronal degeneration in the olfactory bulb (OB). Because DNA base excision repair (BER) is reduced in brain cells during normal aging and AD, we determined whether inefficient BER due to reduced DNA polymerase-β (Polβ) levels renders OB neurons vulnerable to degeneration in the 3xTgAD mouse model of AD.

Mitochondrial SIRT3 Mediates Adaptive Responses of Neurons to Exercise and Metabolic and Excitatory Challenges.

The impact of mitochondrial protein acetylation status on neuronal function and vulnerability to neurological disorders is unknown. Here we show that the mitochondrial protein deacetylase SIRT3 mediates adaptive responses of neurons to bioenergetic, oxidative, and excitatory stress. Cortical neurons lacking SIRT3 exhibit heightened sensitivity to glutamate-induced calcium overload and excitotoxicity and oxidative and mitochondrial stress; AAV-mediated Sirt3 gene delivery restores neuronal stress resistance.

DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes.

We explore the role of DNA damage processing in the progression of cognitive decline by creating a new mouse model. The new model is a cross of a common Alzheimer's disease (AD) mouse (3xTgAD), with a mouse that is heterozygous for the critical DNA base excision repair enzyme, DNA polymerase β. A reduction of this enzyme causes neurodegeneration and aggravates the AD features of the 3xTgAD mouse, inducing neuronal dysfunction, cell death and impairing memory and synaptic plasticity.

Loss of NEIL1 causes defects in olfactory function in mice.

Oxidative DNA damage accumulation has been implicated in neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. The base excision repair pathway is a primary responder to oxidative DNA damage. Effects of loss of base excision repair on normal brain function is a relatively nascent area of research that needs further exploration for better understanding of related brain diseases.

The role of DNA repair in brain related disease pathology.

Oxidative DNA damage is implicated in brain aging, neurodegeneration and neurological diseases. Damage can be created by normal cellular metabolism, which accumulates with age, or by acute cellular stress conditions which create bursts of oxidative damage. Brain cells have a particularly high basal level of metabolic activity and use distinct oxidative damage repair mechanisms to remove oxidative damage from DNA and dNTP pools.

Brain region-specific vulnerability of astrocytes in response to 3-nitropropionic acid is mediated by cytochrome c oxidase isoform expression.

Brain region specificity is a feature characteristic of neurodegenerative disorders, such as Huntington's disease (HD). We have studied the brain region-specific vulnerability of striatal compared with cortical and mesencephalic astrocytes treated with 3-nitropropionic acid (NPA), an in vitro model of HD. Mitochondrial dysfunction is involved in neurodegenerative processes.

Brain region specificity of 3-nitropropionic acid-induced vulnerability of neurons involves cytochrome c oxidase.

Mitochondria play a pivotal role in the regulation of energy metabolism and apoptotic pathways. Properties and functions of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to a different extent to cellular stress and degeneration. We have investigated the effect of 3-nitropropionic acid (NPA), a mitochondrial toxin and mimicking symptoms of Huntington's disease (HD) when applied systemically, on mitochondrial function and viability of primary neurons isolated from mouse brain striatum and cortex.

Gender-specific role of mitochondria in the vulnerability of 6-hydroxydopamine-treated mesencephalic neurons.

Many neurodegenerative diseases, such as Morbus Parkinson, exhibit a gender-dependency showing a higher incidence in men than women. Most of the neurodegenerative disorders involve either causally or consequently a dysfunction of mitochondria. Therefore, neuronal mitochondria may demonstrate a gender-specificity with respect to structural and functional characteristics of these organelles during toxic and degenerative processes.

Cytochrome c oxidase isoform IV-2 is involved in 3-nitropropionic acid-induced toxicity in striatal astrocytes.

Astrocyte mitochondria play an important role for energy supply and neuronal survival in the brain. Toxic and degenerative processes are largely associated with mitochondrial dysfunction. We, therefore, investigated the effect of 3-nitropropionic acid (NPA), a mitochondrial toxin and in vitro model of Huntington's disease (HD), on mitochondrial function and viability of primary striatal astrocytes.