66 results found
De Virgiliis F, Di Giovanni S, 2020, Lung innervation in the eye of a cytokine storm: neuroimmune interactions and COVID-19, NATURE REVIEWS NEUROLOGY, ISSN: 1759-4758
Kong G, Zhou L, Serger E, et 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.
La Montanara P, Hervera A, Baltussen L, et al., 2020, Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models, Science Translational Medicine, Vol: 12, 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.
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.
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.
Palmisano I, Danzi MC, Hutson TH, et 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.
Hervera A, Zhou L, Palmisano I, et 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.
Hervera A, Santos CX, De Virgiliis F, et 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.
Hutson TH, Kathe C, Palmisano I, et 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.
Hervera A, De Virgiliis F, Palmisano I, et 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
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
Hervera A, De Virgiliis F, Palmisano I, et 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-+, ISSN: 1465-7392
Gonzalez-Billault C, Wilson C, Munoz E, et al., 2017, Novel mechanisms involving redox biology are essential to support axonal growth, ISN-ESN Meeting, Publisher: WILEY, Pages: 195-195, ISSN: 0022-3042
Wilson C, Munoz-Palma E, Henriquez DR, et 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.
Joshi Y, Soria MG, Quadrato G, et 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.
Noble M, Mayer-Pröschel M, Li Z, et 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.
Lindner R, Puttagunta R, Tuan N, et al., 2014, DNA methylation temporal profiling following peripheral versus central nervous system axotomy, SCIENTIFIC DATA, Vol: 1, ISSN: 2052-4463
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
Quadrato G, Elnaggar MY, Duman C, et 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
Puttagunta R, Tedeschi A, Soria MG, et al., 2014, PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system, NATURE COMMUNICATIONS, Vol: 5, ISSN: 2041-1723
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
Stern S, Haverkamp S, Sinske D, et al., 2013, The Transcription Factor Serum Response Factor Stimulates Axon Regeneration through Cytoplasmic Localization and Cofilin Interaction., The Journal Of Neuroscience, Vol: 33, Pages: 18836-18848
Lindner R, Puttagunta R, Di Giovanni S, 2013, Epigenetic regulation of axon outgrowth and regeneration in CNS injury: the first steps forward., Neurotherapeutics, Vol: 10, Pages: 771-781
Inadequate axonal sprouting and lack of regeneration limit functional recovery following neurologic injury, such as stroke, brain, and traumatic spinal cord injury. Recently, the enhancement of the neuronal regenerative program has led to promising improvements in axonal sprouting and regeneration in animal models of axonal injury. However, precise knowledge of the essential molecular determinants of this regenerative program remains elusive, thus limiting the choice of fully effective therapeutic strategies. Given that molecular regulation of axonal outgrowth and regeneration requires carefully orchestrated waves of gene expression, both temporally and spatially, epigenetic changes may be an ideal regulatory mechanism to address this unique need. While recent evidence suggests that epigenetic modifications could contribute to the regulation of axonal outgrowth and regeneration following axonal injury in models of stroke, and spinal cord and optic nerve injury, a number of unanswered questions remain. Such questions require systematic investigation of the epigenetic landscape between regenerative and non-regenerative conditions for the potential translation of this knowledge into regenerative strategies in human spinal and brain injury, as well as stroke.
Hart ML, Neumayer KMH, Vaegler M, et al., 2013, Cell-based therapy for the deficient urinary sphincter., Curr Urol Rep, Vol: 14, Pages: 476-487
When sterile culture techniques of mammalian cells first became state of the art, there was tremendous anticipation that such cells could be eventually applied for therapeutic purposes. The discovery of adult human stem or progenitor cells further motivated scientists to pursue research in cell-based therapies. Although evidence from animal studies suggests that application of cells yields measurable benefits, in urology and many other disciplines, progenitor-cell-based therapies are not yet routinely clinically available. Stress urinary incontinence (SUI) is a condition affecting a large number of patients. The etiology of SUI includes, but is not limited to, degeneration of the urinary sphincter muscle tissue and loss of innervation, as well as anatomical and biomechanical causes. Therefore, different regimens were developed to treat SUI. However, at present, a curative functional treatment is not at hand. A progenitor-cell-based therapy that can tackle the etiology of incontinence, rather than the consequences, is a promising strategy. Therefore, several research teams have intensified their efforts to develop such a therapy for incontinence. Here, we introduce candidate stem and progenitor cells suitable for SUI treatment, show how the functional homogeneity and state of maturity of differentiated cells crucial for proper tissue integration can be assessed electrophysiologically prior to their clinical application, and discuss the trophic potential of adult mesenchymal stromal (or stem) cells in regeneration of neuronal function.
Forsberg K, Wuttke A, Quadrato G, et al., 2013, The tumor suppressor p53 fine-tunes reactive oxygen species levels and neurogenesis via PI3 kinase signaling., J Neurosci, Vol: 33, Pages: 14318-14330
Mounting evidence points to a role for endogenous reactive oxygen species (ROS) in cell signaling, including in the control of cell proliferation, differentiation, and fate. However, the function of ROS and their molecular regulation in embryonic mouse neural progenitor cells (eNPCs) has not yet been clarified. Here, we describe that physiological ROS are required for appropriate timing of neurogenesis in the developing telencephalon in vivo and in cultured NPCs, and that the tumor suppressor p53 plays a key role in the regulation of ROS-dependent neurogenesis. p53 loss of function leads to elevated ROS and early neurogenesis, while restoration of p53 and antioxidant treatment partially reverse the phenotype associated with premature neurogenesis. Furthermore, we describe that the expression of a number of neurogenic and oxidative stress genes relies on p53 and that both p53 and ROS-dependent induction of neurogenesis depend on PI3 kinase/phospho-Akt signaling. Our results suggest that p53 fine-tunes endogenous ROS levels to ensure the appropriate timing of neurogenesis in eNPCs. This may also have implications for the generation of tumors of neurodevelopmental origin.
Quadrato G, Di Giovanni S, 2013, Waking up the sleepers: shared transcriptional pathways in axonal regeneration and neurogenesis., Cell Mol Life Sci, Vol: 70, Pages: 993-1007
In the last several years, relevant progress has been made in our understanding of the transcriptional machinery regulating CNS repair after acute injury, such as following trauma or stroke. In order to survive and functionally reconnect to the synaptic network, injured neurons activate an intrinsic rescue program aimed to increase their plasticity. Perhaps, in the attempt to switch back to a plastic and growth-competent state, post-mitotic neurons wake up and re-express a set of transcription factors that are also critical for the regulation of their younger brothers, the neural stem cells. Here, we review and discuss the transcriptional pathways regulating both axonal regeneration and neurogenesis highlighting the connection between the two. Clarification of their common molecular substrate may help simultaneous targeting of both neurogenesis and axonal regeneration with the hope to enhance functional recovery following CNS injury.
Floriddia EM, Rathore KI, Tedeschi A, et al., 2012, p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury, Journal of Neuroscience, Vol: 32, Pages: 13956-13970, ISSN: 0270-6474
Ferreira LMR, Floriddia EM, Quadrato G, et al., 2012, Neural regeneration: lessons from regenerating and non-regenerating systems., Mol Neurobiol, Vol: 46, Pages: 227-241
One only needs to see a salamander regrowing a lost limb to become fascinated by regeneration. However, the lack of robust axonal regeneration models for which good cellular and molecular tools exist has hampered progress in the field. Nevertheless, the nervous system has been revealed to be an excellent model to investigate regeneration. There are conspicuous differences in neuroregeneration capacity between amphibia and warm-blooded animals, as well as between the central and the peripheral nervous systems in mammals. Exploration of such discrepancies led to significant discoveries on the basic tenets of neuroregeneration in the last two decades, identifying several positive and negative regulators of axonal regeneration. Implications of these findings to the comprehension of mammalian regeneration and to the development of spinal cord injury therapies are also addressed.
Beck H, Flynn K, Lindenberg KS, et al., 2012, Serum Response Factor (SRF)-cofilin-actin signaling axis modulates mitochondrial dynamics, Proceedings of the National Academy of Sciences, Vol: 109, Pages: E2523-E2532, ISSN: 0027-8424
<jats:p>Aberrant mitochondrial function, morphology, and transport are main features of neurodegenerative diseases. To date, mitochondrial transport within neurons is thought to rely mainly on microtubules, whereas actin might mediate short-range movements and mitochondrial anchoring. Here, we analyzed the impact of actin on neuronal mitochondrial size and localization. F-actin enhanced mitochondrial size and mitochondrial number in neurites and growth cones. In contrast, raising G-actin resulted in mitochondrial fragmentation and decreased mitochondrial abundance. Cellular F-actin/G-actin levels also regulate serum response factor (SRF)-mediated gene regulation, suggesting a possible link between SRF and mitochondrial dynamics. Indeed, SRF-deficient neurons display neurodegenerative hallmarks of mitochondria, including disrupted morphology, fragmentation, and impaired mitochondrial motility, as well as ATP energy metabolism. Conversely, constitutively active SRF-VP16 induced formation of mitochondrial networks and rescued huntingtin (HTT)-impaired mitochondrial dynamics. Finally, SRF and actin dynamics are connected via the actin severing protein cofilin and its slingshot phosphatase to modulate neuronal mitochondrial dynamics. In summary, our data suggest that the SRF-cofilin-actin signaling axis modulates neuronal mitochondrial function.</jats:p>
Di Giovanni S, Rathore K, 2012, p53-dependent pathways in neurite outgrowth and axonal regeneration, Cell and Tissue Research, Vol: 349, Pages: 87-95, ISSN: 0302-766X
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