Your search for: 'author:("Keeney, Paula M.")' has returned 3 results. (0.009s) Save search

Authors: Bennett, James P. | Keeney, Paula M.

Article Type: Research Article

Abstract: Background: Neuropathological changes of Alzheimer’s disease (AD) and Parkinson’s disease (PD) can coexist in the same sample, suggesting possible common degenerative mechanisms. Objective: The objective of this study was to use RNA-sequencing to compare gene expression in AD and PD vulnerable brain regions and search for co-expressed genes. Methods: Total RNA was isolated from AD/CTL frontal cortex and PD/CTL ventral midbrain. Sequencing libraries were prepared, multiplex paired-end RNA sequencing was carried out, and bioinformatics analyses of gene expression used both publicly available (tophat2/bowtie2/Cufflinks) and commercial (Qlucore Omics Explorer) algorithms. Results: Both AD (frontal cortex, n = 10) and PD (ventral …midbrain, n = 14) samples showed extensive heterogeneity of gene expression. Hierarchical clustering of heatmaps revealed two gene populations (AD, 376 genes; PD, 351 genes) that separated AD or PD from control samples at false-discovery rates (q) of <5% and fold changes of at least 1.3 (AD) or 1.5 (PD). 10,124 genes were co-expressed in our AD and PD samples. A very small group of these genes (n = 23) showed both low variances (<150; variance = standard deviation squared) and reduced expressions (>1.5-fold under-expression) in both AD and PD. Ingenuity Pathways Analyses (IPA, Qiagen) revealed loss of NAD biosynthesis and salvage as the major canonical pathway significantly altered in both AD and PD. Conclusions: AD and PD in vulnerable brain regions appear to arise from and result in independent molecular genetic abnormalities, but we identified several under-expressed genes with potential to treat both diseases. NAD supplementation shows particular promise. Show more

Keywords: Alzheimer’s disease, gene expression, Parkinson’s disease, RNA-sequencing

DOI: 10.3233/ADR-180072

Citation: Journal of Alzheimer's Disease Reports, vol. 2, no. 1, pp. 129-137, 2018

Authors: Thomas, Ravindar R. | Keeney, Paula M. | Bennett, James P.

Article Type: Research Article

Abstract: Parkinson's disease (PD) can include a progressive frontal lobe α-synucleinopathy with disability from cognitive decline and cortico-limbic dysregulation that may arise from bioenergetic impairments. We examined in PD frontal cortex regulation of mitochondrial biogenesis (mitobiogenesis) and its effects on Complex-I. We quantified expression of 33 nuclear genome (nDNA)-encoded and 7 mitochondrial genome (mtDNA)-encoded Complex-I genes, 6 Complex-I assembly factors and multiple mitobiogenesis genes. We related these findings to levels of Complex-I proteins and NADH-driven electron flow in mitochondria from these same specimens reported in earlier studies. We found widespread, decreased expression of nDNA Complex-I genes that correlated in some cases …with mitochondrial Complex-I protein levels, and of ACAD9, a Complex-I assembly factor. mtDNA-transcribed Complex-I genes showed ~ constant expression within each PD sample but variable expression across PD samples that correlated with NRF1. Relationships among PGC-1α and its downstream targets NRF1 and TFAM were very similar in PD and CTL and were related to mitochondrial NADH-driven electron flow. MicroRNA arrays revealed multiple miRNA's regulated >2-fold predicted to interact with PGC-1α or its upstream regulators. Exposure of cultured human neurons to NO, rotenone and TNF-alpha partially reproduced mitobiogenesis down-regulation. In PD frontal cortex mitobiogenesis signaling relationships are maintained but down-regulated, correlate with impaired mitochondrial NADH-driven electron flow and may arise from combinations of nitrosative/oxidative stresses, inflammatory cytokines, altered levels of mitobiogenesis gene-interacting microRNA's, or other unknown mechanisms. Stimulation of mitobiogenesis in PD may inhibit rostral disease progression and appearance of secondary symptoms referable to frontal cortex. Show more

Keywords: Parkinson's disease, mitochondrial biogenesis, Complex-I, gene expression, microRNA

DOI: 10.3233/JPD-2012-11074

Citation: Journal of Parkinson's Disease, vol. 2, no. 1, pp. 67-76, 2012

Authors: Rice, Ann C. | Keeney, Paula M. | Algarzae, Norah K. | Ladd, Amy C. | Thomas, Ravindar R. | Bennett Jr., James P.

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP(+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers …compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1α were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal Aβ1-42 levels. After 48 h exposure of H9 human neural stem cells to the neurotoxic fragment Aβ25-35 , mtDNA copy numbers were not significantly altered. In summary, AD postmortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD. Show more

Keywords: Laser capture microdissection, neural stem cells, PGC1 alpha, real-time PCR, TFAM

DOI: 10.3233/JAD-131715

Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 319-330, 2014