Modulation of Poly ADP Ribose Polymerase (PARP) Levels and Activity by Alcohol Binge-Like Drinking in Male Mice

Vallerini, Gian Paolo; Cheng, You; Chase, Kayla A.; Sharma, Rajiv P.; Kusumo, Handojo; Khakhkhar, Shivani; Feinstein, Douglas L.; Guizzetti, Marina; Gavin, David P.

doi:10.1016/j.neuroscience.2020.09.010

Cited by 3 publications

(16 citation statements)

References 66 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further, we demonstrated the impact of EtOH exposure on the transcript distribution in both the RE and total-RNA pools. Finally, in a direct test of the PARP hypothesis from our lab (Vallerini et al, 2020), we demonstrated that a PARP antagonist (ABT-888) can reverse the effects of EtOH. While this reversal is evident in both fractions, i.e., RE and total-RNA pools, we focused on the normalized RE transcripts to avoid unparameterized variations in the total-RNA pool (elaborated below).…”

Section: Discussionmentioning

confidence: 79%

“…PARP1 repair/activity will induce a reorganization of local chromatin structure, especially in its ability to "parylate" histone proteins, nucleosome disassembly and chromatin relaxation. Consequently, EtOH effects via PARP activity on chromatin and other proteins can be considered to impact both transcription (via 10.3389/fnmol.2023.1125160 chromatin structure) and post-translational modification of nonhistone proteins (via "parylation" of lysine residues) (Vallerini et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Poly-ADP Ribose Polymerase-1 (PARP1) is an enzyme that affects gene expression through histone modification and DNA methylation, among other molecular mechanisms ( Kraus and Hottiger, 2013 ). In C57BL/6J male mice, we recently demonstrated that binge-like alcohol consumption induces PFC PARP mRNA expression and enzymatic activity ( Vallerini et al, 2020 ). Furthermore, virally induced PARP1 overexpression in the PFC increased voluntary alcohol consumption, while the PARP inhibitor ABT-888 decreased it ( Vallerini et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of alcohol and PARP inhibition on RNA ribosomal engagement in cortical excitatory neurons

Krishnan

Vallerini

Gavin

et al. 2023

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

We report on the effects of ethanol (EtOH) and Poly (ADP-ribose) polymerase (PARP) inhibition on RNA ribosomal engagement, as a proxy for protein translation, in prefrontal cortical (PFC) pyramidal neurons. We hypothesized that EtOH induces a shift in RNA ribosomal-engagement (RE) in PFC pyramidal neurons, and that many of these changes can be reversed using a PARP inhibitor. We utilized the translating ribosome affinity purification (TRAP) technique to isolate cell type-specific RNA. Transgenic mice with EGFP-tagged Rpl10a ribosomal protein expressed only in CaMKIIα-expressing pyramidal cells were administered EtOH or normal saline (CTL) i.p. twice a day, for four consecutive days. On the fourth day, a sub-group of mice that received EtOH in the previous three days received a combination of EtOH and the PARP inhibitor ABT-888 (EtOH + ABT-888). PFC tissue was processed to isolate both, CaMKIIα pyramidal cell-type specific ribosomal-engaged RNA (TRAP-RNA), as well as genomically expressed total-RNA from whole tissue, which were submitted for RNA-seq. We observed EtOH effects on RE transcripts in pyramidal cells and furthermore treatment with a PARP inhibitor “reversed” these effects. The PARP inhibitor ABT-888 reversed 82% of the EtOH-induced changes in RE (TRAP-RNA), and similarly 83% in the total-RNA transcripts. We identified Insulin Receptor Signaling as highly enriched in the ethanol-regulated and PARP-reverted RE pool and validated five participating genes from this pathway. To our knowledge, this is the first description of the effects of EtOH on excitatory neuron RE transcripts from total-RNA and provides insights into PARP-mediated regulation of EtOH effects.

show abstract

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of alcohol and PARP inhibition on RNA ribosomal engagement in cortical excitatory neurons

Krishnan

Vallerini

Gavin

et al. 2023

Front. Mol. Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…These results, together, support a crucial role of the TRPM2 channel in mediating EtOH-induced microglial cell death. It is known that exposure to alcohol leads to oxidative stress and activation of PARP [ 8 , 9 , 10 ] and, as introduced earlier, PARP activation is the major signaling mechanism for oxidative stress-induced TRPM2 channel activation, including in microglial cells [ 25 , 26 , 27 , 28 , 29 , 31 , 32 , 33 ]. As described in our recent study examining cell death induced by ROS or Zn 2+ in primary microglial cells [ 25 ], and in this study showing H 2 O 2 -induced cell death in BV2 microglial cells ( Figure 2 e–h), EtOH-induced microglial cell death was remarkably attenuated by treatment with PJ34 and DPQ, two structurally different PARP inhibitors ( Figure 3 ), supporting that PARP activation is critical in EtOH-induced TRPM2-mediated microglial cell death.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, as has been well documented, alcohol intake causes the brain to promote further alcohol consumption [ 7 ]. Regarding how alcohol impacts the brain, multiple molecular and cellular mechanisms have been proposed, including increased poly(ADP-ribose) polymerase (PARP) activity and ensuing regulation of gene expression, induction of oxidative stress via NADPH oxidases (NOX)-mediated generation of reactive oxygen species (ROS), neurotoxicity, neuromodulation, and neuroinflammation [ 7 , 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Ethanol Induces Microglial Cell Death via the NOX/ROS/PARP/TRPM2 Signalling Pathway

et al. 2020

View full text Add to dashboard Cite

Microglial cells are the primary immune cell resident in the brain. Growing evidence indicates that microglial cells play a prominent role in alcohol-induced brain pathologies. However, alcohol-induced effects on microglial cells and the underlying mechanisms are not fully understood, and evidence exists to support generation of oxidative stress due to NADPH oxidases (NOX_-mediated production of reactive oxygen species (ROS). Here, we investigated the role of the oxidative stress-sensitive Ca2+-permeable transient receptor potential melastatin-related 2 (TRPM2) channel in ethanol (EtOH)-induced microglial cell death using BV2 microglial cells. Like H2O2, exposure to EtOH induced concentration-dependent cell death, assessed using a propidium iodide assay. H2O2/EtOH-induced cell death was inhibited by treatment with TRPM2 channel inhibitors and also treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, demonstrating the critical role of PARP and the TRPM2 channel in EtOH-induced cell death. Exposure to EtOH, as expected, led to an increase in ROS production, shown using imaging of 2’,7’-dichlorofluorescein fluorescence. Consistently, EtOH-induced microglial cell death was suppressed by inhibition of NADPH oxidase (NOX) as well as inhibition of protein kinase C. Taken together, our results suggest that exposure to high doses of ethanol can induce microglial cell death via the NOX/ROS/PARP/TRPM2 signaling pathway, providing novel and potentially important insights into alcohol-induced brain pathologies.

show abstract

Ethanol- and PARP-Mediated Regulation of Ribosome-Associated Long Non-Coding RNA (lncRNA) in Pyramidal Neurons

Rizavi,

Gavin,

Krishnan

et al. 2023

ncRNA

Self Cite

View full text Add to dashboard Cite

Although, by definition, long noncoding RNAs (lncRNAs) are not translated, they are sometimes associated with ribosomes. In fact, some estimates suggest the existence of more than 50 K lncRNA molecules that could encode for small peptides. We examined the effects of an ethanol and Poly-ADP Ribose Polymerase (PARP) inhibitor (ABT-888) on ribosome-bound lncRNAs. Mice were administered via intraperitoneal injection (i.p.) either normal saline (CTL) or ethanol (EtOH) twice a day for four consecutive days. On the fourth day, a sub-group of mice administered with ethanol also received ABT-888 (EtOH+ABT). Ribosome-bound lncRNAs in CaMKIIα-expressing pyramidal neurons were measured using the Translating Ribosome Affinity Purification (TRAP) technique. Our findings show that EtOH altered the attachment of 107 lncRNA transcripts, while EtOH+ABT altered 60 lncRNAs. Among these 60 lncRNAs, 49 were altered by both conditions, while EtOH+ABT uniquely altered the attachment of 11 lncRNA transcripts that EtOH alone did not affect. To validate these results, we selected eight lncRNAs (Mir124-2hg, 5430416N02Rik, Snhg17, Snhg12, Snhg1, Mir9-3hg, Gas5, and 1110038B12Rik) for qRT-PCR analysis. The current study demonstrates that ethanol-induced changes in lncRNA attachment to ribosomes can be mitigated by the addition of the PARP inhibitor ABT-888.

show abstract

Modulation of Poly ADP Ribose Polymerase (PARP) Levels and Activity by Alcohol Binge-Like Drinking in Male Mice

Cited by 3 publications

References 66 publications

Effects of alcohol and PARP inhibition on RNA ribosomal engagement in cortical excitatory neurons

Effects of alcohol and PARP inhibition on RNA ribosomal engagement in cortical excitatory neurons

Ethanol Induces Microglial Cell Death via the NOX/ROS/PARP/TRPM2 Signalling Pathway

Ethanol- and PARP-Mediated Regulation of Ribosome-Associated Long Non-Coding RNA (lncRNA) in Pyramidal Neurons

Contact Info

Product

Resources

About