Mitochondrial abnormalities and oxidative stress in Alzheimer's disease

P5 OXIDATIVE STRESS AND PARKINSON’S: LINKING ALPHA-SYNUCLEIN TO EPIGENETICS Almas Siddiqui, Shankar Chinta, Julie Andersen, Ingrid Hanson, and Anand Rane, Buck Institute for Research in Aging We have recently demonstrated increases in nuclear α-synuclein levels and chromatin binding within affected neurons in response to increased oxidative stress in vivo. Preliminary timeof-flight (TOF) mass spectrometric and ChIP-western analyses revealed the presence of the ubiquitin E3 ligase RNF168, monoubiquitinated H2A (µH2A), an epigenetic mark associated with transcriptional “stalling”, and phosphorylated histone variant gamma H2A (γH2X), a modification associated with DNA damage repair, within the alpha-synuclein:DNA complex. Increased presence of this same synuclein-bound complex was also observed in Parkinsonian brain tissues. Recently, DNA damage repair and transcriptional pausing as a consequence of RNF8/RNF168 recruitment have been demonstrated to occur concomitantly on the same stretch of chromosome, raising the intriguing possibility that elevated nuclear levels of either wildtype or mutant protein could result in persistence of dual γH2A and µH2A marks, interfering with both DNA repair and transcriptional events in affected cells. Genome-wide chromatin immunoprecipitation (ChIP)-on-chip analysis revealed that selective alpha-synuclein binding in response to oxidative stress occurs at several promoters including to that for the master mitochondrial transcription activator, PGC1alpha. This coincided with reduced PGC1alpha and PGC1alpha-target gene expression along with impaired mitochondrial function. Exogenous PGC1alpha expression attenuated accompanying neurotoxicity. This suggests that increases in nuclear alpha-synuclein under conditions of oxidative stress may impact on mitochondrial function in part via the protein’s capacity to act as a transcriptional modulator of PGC1alpha. Given the recent identification of PGC1alpha as a therapeutic target for the disorder, this may have important implications for the interplay between oxidative stress and alpha-synuclein in PD.

Julie Andersen

doi:10.1016/j.freeradbiomed.2011.10.009

P6 MITOCHONDRIAL ABNORMALITIES AND OXIDATIVE STRESS IN ALZHEIMER'S DISEASE Xiongwei Zhu, Case Western Reserve University Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized by neurofibrillary tangles, senile plaques and a progressive loss of neuronal cells in selective brain regions. Oxidative stress entails breaching antioxidant defense by excessive oxygen free radical generation to an extent that is sufficient to lead to damage to cellular components. Detection of oxidative damages and accompanying changes in antioxidants and antioxidant enzymes is indicative of oxidative stress. Multiple lines of evidence support an early pathogenic role for oxidative stress in AD such that oxidative stress temporally precedes and also contributes, to the formation of pathological lesions of the disease and oxidative damage involves all categories of biological macromolecules. ROS generation is the unavoidable byproduct of aerobic respiration. As the predominant site of oxidative/energy metabolism within the cell, mitochondria make a significant contribution to oxidative damage and related events. Extensive evidence indicates that cerebral metabolism is reduced, placing mitochondrial dysfunction at the source of increased oxidative stress in AD. In this regard, abnormal mitochondria are a predominant feature in AD and damage to both the components and the structure of mitochondria occur. Also, enhanced mitochondrial fission likely contributes to mitochondrial damage and oxidative stress. Interactions between abnormal mitochondria and disturbed metal homeostasis are likely responsible, at least in part, for cytoplasmic oxidative damage. Evidence for oxidative stress and its likely sources and consequences in relationship to other pathological changes in AD will be discussed. doi:10.1016/j.freeradbiomed.2011.10.010

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Xiongwei Zhu