Imperial College London

ProfessorSimoneDi Giovanni

Faculty of MedicineDepartment of Brain Sciences

Chair in Restorative Neuroscience
 
 
 
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Contact

 

+44 (0)20 7594 3178s.di-giovanni

 
 
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Location

 

E505Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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75 results found

Serger E, Luengo-Gutierrez L, Chadwick JS, Kong G, Zhou L, Crawford G, Danzi MC, Myridakis A, Brandis A, Bello AT, Muller F, Sanchez-Vassopoulos A, De Virgiliis F, Liddell P, Dumas ME, Strid J, Mani S, Dodd D, Di Giovanni Set al., 2022, The gut metabolite indole-3 propionate promotes nerve regeneration and repair, NATURE, Vol: 607, Pages: 585-+, ISSN: 0028-0836

Journal article

Zhou L, Kong G, Palmisano I, Cencioni MT, Danzi M, De Virgiliis F, Chadwick JS, Crawford G, Yu Z, De Winter F, Lemmon V, Bixby J, Puttagunta R, Verhaagen J, Pospori C, Lo Celso C, Strid J, Botto M, Di Giovanni Set al., 2022, Reversible CD8 T cell-neuron cross-talk causes aging-dependent neuronal regenerative decline., Science, Vol: 376, Pages: 1-15, ISSN: 0036-8075

INTRODUCTIONAxonal regeneration and neurological functional recovery are extremely limited in the elderly. Consequently, injuries to the nervous system are typically followed by severe and long-term disability. Our understanding of the molecular mechanisms underlying aging-dependent regenerative failure is poor, hindering progress in the development of effective therapies for neurological repair. To facilitate the design of repair strategies, there is a pressing need to identify critical molecular and cellular mechanisms that cause regenerative failure in aging.RATIONALEAging causes a broad spectrum of modifications in cell signaling, including changes in metabolism, immunity, and overall tissue homeostasis, which play key roles in nervous system physiology and response to insults. Thus, we hypothesized that injuries to the aged nervous system would be followed by unique molecular and cellular modifications that would contribute to aging-dependent regenerative decline. To this end, molecular and cellular signatures associated with aging and injury to the nervous system were systematically investigated by performing RNA sequencing from dorsal root ganglia (DRG) in a well-established model of sciatic nerve injury in young versus aged mice. Insight into these mechanisms could allow the discovery of previously unrecognized molecular targets to counteract aging-dependent regenerative decline.RESULTSInitial analysis of RNA sequencing data identified that aging was mainly associated with a marked increase in T cell activation and signaling in DRG after sciatic nerve injury in mice. Subsequent experiments demonstrated that aging was associated with increased inflammatory cytokines including lymphotoxins in DRG both preceding and following sciatic nerve injury. Specifically, we found that lymphotoxin β was required for the phosphorylation of NF-κB that drives the expression of the chemokine CXCL13 in DRG sensory neurons. CXCL13 attracted CD8+ T cells that expresse

Journal article

Koehl G, Goding J, Di Giovanni S, Green Ret al., 2022, SELF-ASSEMBLED CONDUCTIVE NANOFIBERS FOR SPINAL CORD REGENERATION, Publisher: MARY ANN LIEBERT, INC, Pages: S188-S188, ISSN: 1937-3341

Conference paper

Kong G, Zhou L, Freiwald A, Shkura K, Di Giovanni Set al., 2022, Purification of mouse axoplasmic proteins from dorsal root ganglia nerves for proteomics analysis., STAR Protoc, Vol: 3

The study of neuronal signaling ex vivo requires the identification of the proteins that are represented within the neuronal axoplasm. Here, we describe a detailed protocol to isolate the axoplasm of peripheral and central axonal branches of sciatic dorsal root ganglia neurons in mice. The axoplasm is separated by 2D gel and digestion followed by proteomics analysis with MS/MS-LC. This protocol can be applied to dissect the axoplasmic protein expression signatures before and after a sciatic nerve or a spinal cord injury. For complete details on the use and execution of this protocol, please refer to Kong et al. (2020).

Journal article

Nagy I, Irfan J, Febrianto M, Sharma A, Rose T, Mahmudzade Y, Di Giovanni S, Torres-Perez Jet al., 2022, DNA methylation and non-coding RNAs during tissue-injury associated pain, International Journal of Molecular Sciences, Vol: 23, Pages: 1-29, ISSN: 1422-0067

While about half of the population experience persistent pain associated with tissue damages during their lifetime, current symptom-based approaches often fail to reduce such pain to a satisfactory level. To provide better patient care, mechanism-based analgesic approaches must be developed, which necessitates a comprehensive understanding of the nociceptive mechanism leading to tissue injury-associated persistent pain. Epigenetic events leading the altered transcription in the nervous system are pivotal in the maintenance of pain in tissue injury. However, the mechanisms through which those events contribute to the persistence of pain are not fully understood. This review provides a summary and critical evaluation of two epigenetic mechanisms, DNA methylation and non-coding RNA expression, on transcriptional modulation in nociceptive pathways during the development of tissue injury-associated pain. We assess the pre-clinical data and their translational implication and evaluate the potential of controlling DNA methylation and non-coding RNA expression as novel analgesic approaches and/or biomarkers of persistent pain.

Journal article

Hervera A, De Virgiliis F, Palmisano I, Zhou L, Tantardini E, Kong G, Hutson T, Danzi MC, Perry RB-T, Santos CXC, Antonio Del Rio J, Carroll T, Lemmon V, Bixby JL, Shah AM, Fainzilber M, Di Giovanni Set al., 2021, NOX-dependent reactive oxygen species are essential regulators of axonal regeneration, Annual Meeting of the Society-for-Free-Radical-Research-Europe (SFRR-E) - Redox Biology in the 21st Century - A New Scientific Discipline, Publisher: ELSEVIER SCIENCE INC, Pages: S9-S11, ISSN: 0891-5849

Conference paper

Torres Perez J, Irfan J, Febrianto MR, Di Giovanni S, Nagy Iet al., 2021, Histone post-translational modification as potential therapeutic targets for pain management, Trends in Pharmacological Sciences, Vol: 42, Pages: 897-911, ISSN: 0165-6147

Effective pharmacological management of pain associated with tissue unmet medical need. Transcriptional modifications in nociceptive pathways are pivotal for the development and the maintenance of pain associated with tissue damage. Accumulating evidence has shown the importance of the epigenetic control of transcription within nociceptive pathways via histone post-translational modifications (PTMs). Hence, histone PTMs could be targets for novel effective analgesics. Here, we discuss the current understanding of histone PTMs in the modulation of gene expression affecting nociception and pain phenotypes following tissue injury. We also provide a critical view of the translational implications of preclinical models and discuss opportunities and challenges of targeting histone PTMs for relieving pain in clinically relevant tissue injuries.

Journal article

De Virgiliis F, Di Giovanni S, 2021, Reply to: Neuroimmune interactions and COVID-19 in lung transplant recipients, NATURE REVIEWS NEUROLOGY, Vol: 17, Pages: 325-326, ISSN: 1759-4758

Journal article

De Virgiliis F, Hutson TH, Palmisano I, Amachree S, Miao J, Zhou L, Todorova R, Thompson R, Danzi MC, Lemmon VP, Bixby JL, Wittig I, Shah AM, Di Giovanni Set al., 2020, Enriched conditioning expands the regenerative ability of sensory neurons after spinal cord injury via neuronal intrinsic redox signaling, NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723

Journal article

De Virgiliis F, Di Giovanni S, 2020, Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19, NATURE REVIEWS NEUROLOGY, Vol: 16, Pages: 645-652, ISSN: 1759-4758

Journal article

Kong G, Zhou L, Serger E, Palmisano I, De Virgiliis F, Hutson TH, Mclachlan E, Freiwald A, La Montanara P, Shkura K, Puttagunta R, Di Giovanni Set al., 2020, AMPK controls the axonal regenerative ability of dorsal root ganglia sensory neurons after spinal cord injury., Nature Metabolism, Vol: 2, Pages: 918-933, ISSN: 2522-5812

Regeneration after injury occurs in axons that lie in the peripheral nervous system but fails in the central nervous system, thereby limiting functional recovery. Differences in axonal signalling in response to injury that might underpin this differential regenerative ability are poorly characterized. Combining axoplasmic proteomics from peripheral sciatic or central projecting dorsal root ganglion (DRG) axons with cell body RNA-seq, we uncover injury-dependent signalling pathways that are uniquely represented in peripheral versus central projecting sciatic DRG axons. We identify AMPK as a crucial regulator of axonal regenerative signalling that is specifically downregulated in injured peripheral, but not central, axons. We find that AMPK in DRG interacts with the 26S proteasome and its CaMKIIα-dependent regulatory subunit PSMC5 to promote AMPKα proteasomal degradation following sciatic axotomy. Conditional deletion of AMPKα1 promotes multiple regenerative signalling pathways after central axonal injury and stimulates robust axonal growth across the spinal cord injury site, suggesting inhibition of AMPK as a therapeutic strategy to enhance regeneration following spinal cord injury.

Journal article

La Montanara P, Hervera A, Baltussen L, Hutson TH, Palmisano I, De Virgiliis F, Gao Y, Bartus K, Majid Q, Gorgoraptis N, Wong K, Downs J, Pizzorusso T, Ultanir S, Leonard H, Yu H, Millar DS, Nagy I, Mazarakis N, Di Giovanni Set al., 2020, Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models, Science Translational Medicine, Vol: 12, Pages: 1-11, ISSN: 1946-6234

Cyclin-dependent-like kinase 5 (Cdkl5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognised anamnestic deficiency in pain perception. Consistent with a role in nociception, we discovered that Cdkl5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in iPS-derived human nociceptors. CDKL5 deficient mice display defective epidermal innervation and conditional deletion of Cdkl5 in DRG sensory neurons significantly impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, Cdkl5 interacts with CaMKIIα to control outgrowth as well as TRPV1-dependent signalling, which are disrupted in both Cdkl5 mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for Cdkl5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder.

Journal article

Bradke F, Di Giovanni S, Fawcett J, 2020, Neuronal maturation: challenges and opportunities in a nascent field, Trends in Neurosciences, Vol: 43, Pages: 360-362, ISSN: 0166-2236

After its initial development, the nervous system matures to connect and shape the neuronal circuitry and to keep it functional in humans for decades. Here we conceptualize neuronal maturation as a research field that will have, we would argue, a strong impact on understanding the healthy and diseased nervous system. Identifying the key mechanisms underlying neuronal maturation has the potential to reverse this process in adulthood, thereby facilitating regeneration.

Journal article

Hutson TH, Di Giovanni S, 2019, The translational landscape in spinal cord injury: focus on neuroplasticity and regeneration, Nature Reviews Neurology, Vol: 15, Pages: 732-745, ISSN: 1759-4758

Over the past decade, we have witnessed a flourishing of novel strategies to enhance neuroplasticity and promote axon regeneration following spinal cord injury, and results from preclinical studies suggest that some of these strategies have the potential for clinical translation. Spinal cord injury leads to the disruption of neural circuitry and connectivity, resulting in permanent neurological disability. Recovery of function relies on augmenting neuroplasticity to potentiate sprouting and regeneration of spared and injured axons, to increase the strength of residual connections and to promote the formation of new connections and circuits. Neuroplasticity can be fostered by exploiting four main biological properties: neuronal intrinsic signalling, the neuronal extrinsic environment, the capacity to reconnect the severed spinal cord via neural stem cell grafts, and modulation of neuronal activity. In this Review, we discuss experimental evidence from rodents, nonhuman primates and patients regarding interventions that target each of these four properties. We then highlight the strengths and challenges of individual and combinatorial approaches with respect to clinical translation. We conclude by considering future developments and providing views on how to bridge the gap between preclinical studies and clinical translation.

Journal article

Palmisano I, Danzi MC, Hutson TH, Zhou L, McLachlan E, Serger E, Shkura K, Srivastava PK, Hervera A, Neill NO, Liu T, Dhrif H, Wang Z, Kubat M, Wuchty S, Merkenschlager M, Levi L, Elliott E, Bixby JL, Lemmon VP, Di Giovanni Set al., 2019, Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons, Nature Neuroscience, Vol: 22, Pages: 1913-1924, ISSN: 1097-6256

Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.

Journal article

Hervera A, Zhou L, Palmisano I, McLachlan E, Kong G, Hutson TH, Danzi MC, Lemmon VP, Bixby JL, Matamoros-Angles A, Forsberg K, De Virgiliis F, Matheos DP, Kwapis J, Wood MA, Puttagunta R, Del Río JA, Di Giovanni Set al., 2019, PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure, EMBO Journal, Vol: 38, ISSN: 0261-4189

The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration‐competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration‐incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with small‐molecule inhibitors targeting key epigenetic enzymes in DRG neurons, we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. In vivo, we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3, thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4‐dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.

Journal article

Hervera A, Santos CX, De Virgiliis F, Shah AM, Di Giovanni Set al., 2019, Paracrine mechanism of redox signalling for post-mitotic cell and tissue regeneration, Trends in Cell Biology, Vol: 29, Pages: 514-530, ISSN: 0962-8924

Adult postmitotic mammalian cells, including neurons and cardiomyocytes, have a limited capacity to regenerate after injury. Therefore, an understanding of the molecular mechanisms underlying their regenerative ability is critical to advance tissue repair therapies. Recent studies highlight how redox signalling via paracrine cell-to-cell communication may act as a central mechanism coupling tissue injury with regeneration. Post-injury redox paracrine signalling can act by diffusion to nearby cells, through mitochondria or within extracellular vesicles, affecting specific intracellular targets such as kinases, phosphatases, and transcription factors, which in turn trigger a regenerative response. Here, we review redox paracrine signalling mechanisms in postmitotic tissue regeneration and discuss current challenges and future directions.

Journal article

Hutson TH, Kathe C, Palmisano I, Bartholdi K, Hervera A, De Virgiliis F, Mclachlan E, Zhou L, Kong G, Barraud Q, Danzi MC, Medrano-Fernandez A, Lopez-Atalaya JP, Boutillier AL, Sinha SH, Singh AK, Chaturbedy P, Moon LDF, Kundu TK, Bixby JL, Lemmon VP, Barco A, Courtine G, Di Giovanni Set al., 2019, Cbp-dependent histone acetylation mediates axon regeneration induced by environmental enrichment in rodent spinal cord injury models, Science Translational Medicine, Vol: 11, ISSN: 1946-6234

After a spinal cord injury, axons fail to regenerate in the adult mammalian central nervous system, leading to permanent deficits in sensory and motor functions. Increasing neuronal activity after an injury using electrical stimulation or rehabilitation can enhance neuronal plasticity and result in some degree of recovery; however, the underlying mechanisms remain poorly understood. We found that placing mice in an enriched environment before an injury enhanced the activity of proprioceptive dorsal root ganglion neurons, leading to a lasting increase in their regenerative potential. This effect was dependent on Creb-binding protein (Cbp)–mediated histone acetylation, which increased the expression of genes associated with the regenerative program. Intraperitoneal delivery of a small-molecule activator of Cbp at clinically relevant times promoted regeneration and sprouting of sensory and motor axons, as well as recovery of sensory and motor functions in both the mouse and rat model of spinal cord injury. Our findings showed that the increased regenerative capacity induced by enhancing neuronal activity is mediated by epigenetic reprogramming in rodent models of spinal cord injury. Understanding the mechanisms underlying activity-dependent neuronal plasticity led to the identification of potential molecular targets for improving recovery after spinal cord injury.

Journal article

Hervera A, De Virgiliis F, Palmisano I, Zhou L, Tantardini E, Kong G, Hutson T, Danzi MC, Perry RB-T, Santos CXC, Kapustin AN, Fleck RA, Del Rio JA, Carroll T, Lemmon V, Bixby JL, Shah AM, Fainzilber M, Di Giovanni Set al., 2018, Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons (vol 20, pg 307, 2018), NATURE CELL BIOLOGY, Vol: 20, Pages: 1098-1098, ISSN: 1465-7392

Journal article

Palmisano I, Di Giovanni S, 2018, Advances and Limitations of Current Epigenetic Studies Investigating Mammalian Axonal Regeneration, NEUROTHERAPEUTICS, Vol: 15, Pages: 529-540, ISSN: 1933-7213

Journal article

Hervera A, De Virgiliis F, Palmisano I, Zhou L, Tantardini E, Kong G, Hutson T, Danzi MC, Perry RB-T, Santos CXC, Kapustin AN, Fleck RA, Antonio Del Rio J, Carroll T, Lemmon V, Bixby JL, Shah AM, Fainzilber M, Di Giovanni Set al., 2018, Reactive oxygen species regulate axonal regeneration through the release of exosomal NADPH oxidase 2 complexes into injured axons, Nature Cell Biology, Vol: 20, Pages: 307-319, ISSN: 1465-7392

Reactive oxygen species (ROS) contribute to tissue damage and remodelling mediated by the inflammatory response after injury. Here we show that ROS, which promote axonal dieback and degeneration after injury, are also required for axonal regeneration and functional recovery after spinal injury. We find that ROS production in the injured sciatic nerve and dorsal root ganglia requires CX3CR1-dependent recruitment of inflammatory cells. Next, exosomes containing functional NADPH oxidase 2 complexes are released from macrophages and incorporated into injured axons via endocytosis. Once in axonal endosomes, active NOX2 is retrogradely transported to the cell body through an importin-β1–dynein-dependent mechanism. Endosomal NOX2 oxidizes PTEN, which leads to its inactivation, thus stimulating PI3K–phosporylated (p-)Akt signalling and regenerative outgrowth. Challenging the view that ROS are exclusively involved in nerve degeneration, we propose a previously unrecognized role of ROS in mammalian axonal regeneration through a NOX2–PI3K–p-Akt signalling pathway.

Journal article

Gonzalez-Billault C, Wilson C, Munoz E, Nunez T, di Giovanni Set al., 2017, Novel mechanisms involving redox biology are essential to support axonal growth, ISN-ESN Meeting, Publisher: WILEY, Pages: 195-195, ISSN: 0022-3042

Conference paper

Wilson C, Munoz-Palma E, Henriquez DR, Palmisano I, Tulio Nunez M, Di Giovanni S, Gonzalez-Billault Cet al., 2016, A Feed-Forward Mechanism Involving the NOX Complex and RyR-Mediated Ca2+ Release During Axonal Specification, Journal of Neuroscience, Vol: 36, Pages: 11107-11119, ISSN: 1529-2401

Physiological levels of ROS support neurite outgrowth and axonal specification, but the mechanisms by which ROS are able to shapeneurons remain unknown. Ca 2, a broad intracellular second messenger, promotes both Rac1 activation and neurite extension. Ca 2releasefromthe endoplasmic reticulum, mediated by boththe IP3R1 and ryanodine receptor (RyR) channels, requires physiological ROSlevels that are mainly sustained by the NADPH oxidase (NOX) complex. In this work, we explore the contribution of the link betweenNOX and RyR-mediated Ca 2 release toward axonal specification of rat hippocampal neurons. Using genetic approaches, we findthatNOX activation promotes both axonal development and Rac1 activationthrough a RyR-mediatedmechanism,whichinturn activatesNOX through Rac1, one of the NOX subunits. Collectively, these data suggest a feedforward mechanism that integrates both NOX activityand RyR-mediated Ca 2 release to support cellular mechanisms involved in axon development.

Journal article

Joshi Y, Soria MG, Quadrato G, Inak G, Zhou L, Hervera A, Rathore KI, Elnaggar M, Magali C, Marine JC, Puttagunta R, Di Giovanni Set al., 2015, The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury, Brain, Vol: 138, Pages: 1843-1862, ISSN: 0006-8950

Regeneration of injured central nervous system axons is highly restricted, causing neurological impairment. To date, although the lack of intrinsic regenerative potential is well described, a key regulatory molecular mechanism for the enhancement of both axonal regrowth and functional recovery after central nervous system injury remains elusive. While ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development as well as after axonal injury, their role specifically in axonal regeneration is unknown. Following a bioinformatics network analysis combining ubiquitin ligases with previously defined axonal regenerative proteins, we found a triad composed of the ubiquitin ligases MDM4, MDM2 and the transcription factor p53 (encoded by TP53) as a putative central signalling complex restricting the regeneration program. Indeed, conditional deletion of MDM4 or pharmacological inhibition of MDM2/p53 interaction in the eye and spinal cord promote axonal regeneration and sprouting of the optic nerve after crush and of supraspinal tracts after spinal cord injury. The double conditional deletion of MDM4-p53 as well as MDM2 inhibition in p53-deficient mice blocks this regenerative phenotype, showing its dependence upon p53. Genome-wide gene expression analysis from ex vivo fluorescence-activated cell sorting in MDM4-deficient retinal ganglion cells identifies the downstream target IGF1R, whose activity and expression was found to be required for the regeneration elicited by MDM4 deletion. Importantly, we demonstrate that pharmacological enhancement of the MDM2/p53-IGF1R axis enhances axonal sprouting as well as functional recovery after spinal cord injury. Thus, our results show MDM4-MDM2/p53-IGF1R as an original regulatory mechanism for CNS regeneration and offer novel targets to enhance neurological recovery.

Journal article

Noble M, Mayer-Pröschel M, Li Z, Dong T, Cui W, Pröschel C, Ambeskovic I, Dietrich J, Han R, Yang YM, Folts C, Stripay J, Chen H-Y, Stevens BMet al., 2015, Redox biology in normal cells and cancer: restoring function of the redox/Fyn/c-Cbl pathway in cancer cells offers new approaches to cancer treatment., Free Radic Biol Med, Vol: 79, Pages: 300-323

This review discusses a unique discovery path starting with novel findings on redox regulation of precursor cell and signaling pathway function and identification of a new mechanism by which relatively small changes in redox status can control entire signaling networks that regulate self-renewal, differentiation, and survival. The pathway central to this work, the redox/Fyn/c-Cbl (RFC) pathway, converts small increases in oxidative status to pan-activation of the c-Cbl ubiquitin ligase, which controls multiple receptors and other proteins of central importance in precursor cell and cancer cell function. Integration of work on the RFC pathway with attempts to understand how treatment with systemic chemotherapy causes neurological problems led to the discovery that glioblastomas (GBMs) and basal-like breast cancers (BLBCs) inhibit c-Cbl function through altered utilization of the cytoskeletal regulators Cool-1/βpix and Cdc42, respectively. Inhibition of these proteins to restore normal c-Cbl function suppresses cancer cell division, increases sensitivity to chemotherapy, disrupts tumor-initiating cell (TIC) activity in GBMs and BLBCs, controls multiple critical TIC regulators, and also allows targeting of non-TICs. Moreover, these manipulations do not increase chemosensitivity or suppress division of nontransformed cells. Restoration of normal c-Cbl function also allows more effective harnessing of estrogen receptor-α (ERα)-independent activities of tamoxifen to activate the RFC pathway and target ERα-negative cancer cells. Our work thus provides a discovery strategy that reveals mechanisms and therapeutic targets that cannot be deduced by standard genetics analyses, which fail to reveal the metabolic information, isoform shifts, protein activation, protein complexes, and protein degradation critical to our discoveries.

Journal article

Lindner R, Puttagunta R, Tuan N, Di Giovanni Set al., 2014, DNA methylation temporal profiling following peripheral versus central nervous system axotomy, SCIENTIFIC DATA, Vol: 1, ISSN: 2052-4463

Journal article

Forsberg K, Di Giovanni S, 2014, Cross Talk between Cellular Redox Status, Metabolism, and p53 in Neural Stem Cell Biology, NEUROSCIENTIST, Vol: 20, Pages: 326-342, ISSN: 1073-8584

Journal article

Quadrato G, Elnaggar MY, Duman C, Sabino A, Forsberg K, Di Giovanni Set al., 2014, Modulation of GABAA Receptor Signaling Increases Neurogenesis and Suppresses Anxiety through NFATc4, JOURNAL OF NEUROSCIENCE, Vol: 34, Pages: 8630-8645, ISSN: 0270-6474

Journal article

Puttagunta R, Tedeschi A, Soria MG, Hervera A, Lindner R, Rathore KI, Gaub P, Joshi Y, Tuan N, Schmandke A, Laskowski CJ, Boutillier A-L, Bradke F, Di Giovanni Set al., 2014, PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system, Nature Communications, Vol: 5, ISSN: 2041-1723

Axonal regenerative failure is a major cause of neurological impairment following central nervous system (CNS) but not peripheral nervous system (PNS) injury. Notably, PNS injury triggers a coordinated regenerative gene expression programme. However, the molecular link between retrograde signalling and the regulation of this gene expression programme that leads to the differential regenerative capacity remains elusive. Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. Thus, we find a specific epigenetic mechanism that regulates axonal regeneration of CNS axons, suggesting novel targets for clinical application.

Journal article

Quadrato G, Elnaggar MY, Di Giovanni S, 2014, Adult neurogenesis in brain repair: cellular plasticity vs. cellular replacement, FRONTIERS IN NEUROSCIENCE, Vol: 8, ISSN: 1662-453X

Journal article

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