13 research outputs found

    Impact of Alcohol Abuse on Susceptibility to Rare Neurodegenerative Diseases

    Get PDF
    Despite the prevalence and well-recognized adverse effects of prenatal alcohol exposure and alcohol use disorder in the causation of numerous diseases, their potential roles in the etiology of neurodegenerative diseases remain poorly characterized. This is especially true of the rare neurodegenerative diseases, for which small population sizes make it difficult to conduct broad studies of specific etiological factors. Nonetheless, alcohol has potent and long-lasting effects on neurodegenerative substrates, at both the cellular and systems levels. This review highlights the general effects of alcohol in the brain that contribute to neurodegeneration across diseases, and then focuses on specific diseases in which alcohol exposure is likely to play a major role. These specific diseases include dementias (alcohol-induced, frontotemporal, and Korsakoff syndrome), ataxias (cerebellar and frontal), and Niemann-Pick disease (primarily a Type B variant and Type C). We conclude that there is ample evidence to support a role of alcohol abuse in the etiology of these diseases, but more work is needed to identify the primary mechanisms of alcohol’s effects

    Live-Cell Monitoring of Periodic Gene Expression in Synchronous Human Cells Identifies Forkhead Genes involved in Cell Cycle Control

    Get PDF
    We developed a system to monitor periodic luciferase activity from cell cycle-regulated promoters in synchronous cells. Reporters were driven by a minimal human E2F1 promoter with peak expression in G1/S or a basal promoter with six Forkhead DNA-binding sites with peak expression at G2/M. After cell cycle synchronization, luciferase activity was measured in live cells at 10-min intervals across three to four synchronous cell cycles, allowing unprecedented resolution of cell cycle-regulated gene expression. We used this assay to screen Forkhead transcription factors for control of periodic gene expression. We confirmed a role for FOXM1 and identified two novel cell cycle regulators, FOXJ3 and FOXK1. Knockdown of FOXJ3 and FOXK1 eliminated cell cycle-dependent oscillations and resulted in decreased cell proliferation rates. Analysis of genes regulated by FOXJ3 and FOXK1 showed that FOXJ3 may regulate a network of zinc finger proteins and that FOXK1 binds to the promoter and regulates DHFR, TYMS, GSDMD, and the E2F binding partner TFDP1. Chromatin immunoprecipitation followed by high-throughput sequencing analysis identified 4329 genomic loci bound by FOXK1, 83% of which contained a FOXK1-binding motif. We verified that a subset of these loci are activated by wild-type FOXK1 but not by a FOXK1 (H355A) DNA-binding mutant

    Modulation of Clock Gene Expression by the Transcriptional Coregulator Receptor Interacting Protein 140 (RIP140)

    Get PDF
    Circadian rhythms are generated in central and peripheral tissues by an intracellular oscillating timing mechanism known as the circadian clock. Several lines of evidence show a strong and bidirectional interplay between metabolism and circadian rhythms. Receptor interacting protein 140 (RIP140) is a coregulator for nuclear receptors and other transcription factors that represses catabolic pathways in metabolic tissues. Although RIP140 functions as a corepressor for most nuclear receptors, mounting evidence points to RIP140 as a dual coregulator that can repress or activate different sets of genes. Here, we demonstrate that RIP140 mRNA and protein levels are under circadian regulation and identify RIP140 as a modulator of clock gene expression, suggesting that RIP140 can participate in a feedback mechanism affecting the circadian clock. We show that the absence of RIP140 disturbs the basal levels of BMAL1 and other clock genes, reducing the amplitude of their oscillations. In addition, we demonstrate that RIP140 is recruited to retinoid-related orphan receptor (ROR) binding sites on the BMAL1 promoter, directly interacts with RORα, and increases transcription from the BMAL1 promoter in a RORα-dependent manner. These results indicate that RIP140 is not only involved in metabolic control but also acts as a coactivator for RORα, influencing clock gene expression

    Aberrant \u3ci\u3eAZIN2\u3c/i\u3e and Polyamine Metabolism Precipitates Tau Neuropathology

    Get PDF
    Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell’s response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer’s disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD

    Retinoic Acid Mediates Long-Paced Oscillations in Retinoid Receptor Activity: Evidence for a Potential Role for RIP140

    Get PDF
    Mechanisms that underlie oscillatory transcriptional activity of nuclear receptors (NRs) are incompletely understood. Evidence exists for rapid, cyclic recruitment of coregulatory complexes upon activation of nuclear receptors. RIP140 is a NR coregulator that represses the transactivation of agonist-bound nuclear receptors. Previously, we showed that RIP140 is inducible by all-trans retinoic acid (RA) and mediates limiting, negative-feedback regulation of retinoid signaling.Here we report that in the continued presence of RA, long-paced oscillations of retinoic acid receptor (RAR) activity occur with a period ranging from 24 to 35 hours. Endogenous expression of RIP140 and other RA-target genes also oscillate in the presence of RA. Cyclic retinoid receptor transactivation is ablated by constitutive overexpression of RIP140. Further, depletion of RIP140 disrupts cyclic expression of the RA target gene HOXA5. Evidence is provided that RIP140 may limit RAR signaling in a selective, non-redundant manner in contrast to the classic NR coregulators NCoR1 and SRC1 that are not RA-inducible, do not cycle, and may be partially redundant in limiting RAR activity. Finally, evidence is provided that RIP140 can repress and be induced by other nuclear receptors in a manner that suggests potential participation in other NR oscillations.We provide evidence for novel, long-paced oscillatory retinoid receptor activity and hypothesize that this may be paced in part, by RIP140. Oscillatory NR activity may be involved in mediating hormone actions of physiological and pathological importance

    Study of the Roles of LRBA in Cancer Cell Proliferation and SHIP-1 in NK Cell Function

    Get PDF
    LRBA (LPS Responsive Beige-like Protein Kinase A anchor) gene expression is induced by the mitogen LPS and is a member of the WBW gene family member which is comprised of genes that are involved in cellular proliferation and differentiation. This work provides evidence for the over-expression of LRBA in certain cancers, and that LRBA promoter activity and endogenous LRBA mRNA levels are negatively regulated by the tumor suppressor p53 and positively regulated by E2F transactivators. Furthermore, we demonstrate that inhibition of LRBA expression or function leads to decreased proliferation of cancer cells and that LRBA plays a role in the EGFR signal transduction pathway. In addition to the findings of LRBA’s role in carcinogenesis, this work also shows evidence of the knockdown of the SH2-containing Inositol 5’ Phosphatase (SHIP) in both mouse and human cells. Furthermore, we provide evidence that SHIP-1 is involved in the AKT signal transduction pathway in human Natural Killer cells

    Chronic shifts in the length and phase of the light cycle increase intermittent alcohol drinking in C57BL/6J mice

    No full text
    Introduction: Shift workers – e.g., health care professionals, truck drivers, and factory workers – are forced to maintain daily cycles at odds with their natural circadian rhythms and as a consequence need to frequently readjust these cycles. This shift work-induced circadian desynchrony (CD) is associated with increased sleep disorders and with alcohol abuse. Nonetheless, it has proven difficult to model CD-induced changes in alcohol consumption in mouse models, which is an important step toward identifying the mechanisms by which CD increases alcohol intake. This study examined whether frequent changes in the light cycle could increase free access alcohol intake in a mouse line that readily consumes alcohol. Methods: Free access alcohol intake, water intake, and wheel-running activity patterns of male C57BL/6J mice were measured while the mice were maintained on a normal 12HR photoperiod for baseline data for two weeks. The mice were then exposed to an alternating photoperiod of 12 hours and 18 hours, with light onset advanced 8 hours during the 18HR photoperiod. The photoperiods rotated every three days, for 21 days total. Results: The repeated pattern of phase advances and delays, with a concurrent change in the length of the photoperiod, shifted mice to a pattern of bingeintermittent drinking alcoholalcohol drinking without altering water intake. Wheel running activity demonstrated that mice were unable to reset their behavioral clocks during CD, showing constant, low-level activity with no peak in activity at the start of the dark phase and greater activity during the morning light phase. Conclusion: It is possible to model CD effects on alcohol intake in C57BL/6J mice using a pattern of phase shifts and changes in the photoperiod. Using this model, we demonstrate that mice begin intermittent drinking during CD, and this increase in alcohol intake does not correlate with an increase in overall activity or in overall fluid intake
    corecore