Marina Melone

Professor of Neurology
Former Director of the CIRN

Name Marina
Surname Melone
Institution Università degli Studi della Campania Luigi Vanvitelli
Telephone +39 081 566 6810
Mobile +39 333 956 6365
Address Department of Medical, Surgical, Neurological, Metabolic Sciences, and Aging, 2nd Division of Neurology, Center for Rare Diseases, University of Campania "Luigi Vanvitelli", Napoli, Italy
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Marina Melone


  • Foix-Chavany-Marie syndrome in a 17-year-old female with congenital cytomegalovirus infection.

    Publication Date: 20/11/2014 on Neuropsychiatric disease and treatment
    by Conforti R, Capasso R, Capaldo G, Dato C, Saracino D, Di Iorio G, Melone MA
    DOI: 10.2147/NDT.S68098

    Foix-Chavany-Marie syndrome is characterized by bilateral facio-glosso-pharyngo-masticatory paralysis of voluntary movement due to bilateral anterior opercular lesions. We describe the case of a 17-year-old female affected by Foix-Chavany-Marie syndrome and congenital cytomegalovirus infection, evaluating the possible etiopathogenetic correlation between cerebral cortical dysplasia and intrauterine infections.

  • Unusual Stüve-Wiedemann syndrome with complete maternal chromosome 5 isodisomy.

    Publication Date: 01/11/2014 on Annals of clinical and translational neurology
    by Melone MA, Pellegrino MJ, Nolano M, Habecker BA, Johansson S, Nathanson NM, Knappskog PM, Hahn AF, Boman H
    DOI: 10.1002/acn3.126

    A woman was isozygous for a novel mutation in the leukemia inhibitory factor receptor gene (LIFR) (c.2170C>G; p.Pro724Ala) which disrupts LIFR downstream signaling and results in Stüve-Wiedemann syndrome (STWS). She inherited two identical chromosomes 5 from her mother, heterozygous for the LIFR mutation. The presentation was typical for STWS, except there was no long bone dysplasia. Prominent cold-induced sweating and heat intolerance lead to an initial diagnosis of cold-induced sweating syndrome, excluded by exome sequencing. Skin biopsies provide the first human evidence of failed postnatal cholinergic differentiation of sympathetic neurons innervating sweat glands in cold-induced sweating, and of a neuropathy.

  • High grade glioblastoma is associated with aberrant expression of ZFP57, a protein involved in gene imprinting, and of CPT1A and CPT1C that regulate fatty acid metabolism.

    Publication Date: 01/06/2014 on Cancer biology & therapy
    by Cirillo A, Di Salle A, Petillo O, Melone MA, Grimaldi G, Bellotti A, Torelli G, De' Santi MS, Cantatore G, Marinelli A, Galderisi U, Peluso G
    DOI: 10.4161/cbt.28408

    The diagnosis of glioblastoma is still based on tumor histology, but emerging molecular diagnosis is becoming an important part of glioblastoma classification. Besides the well-known cell cycle-related circuitries that are associated with glioblastoma onset and development, new insights may be derived by looking at pathways involved in regulation of epigenetic phenomena and cellular metabolism, which may both be highly deregulated in cancer cells. We evaluated if in glioblastoma patients the high grade of malignancy could be associated with aberrant expression of some genes involved in regulation of epigenetic phenomena and lipid metabolism. We measured the mRNA levels of ZFP57, TRIM28, CPT1A, CPT1B, and CPT1C in a cohort of 80 patients divided in two groups: grade II and grade IV. We evidenced that high grade glioblastoma is associated with increased level of ZFP57, a protein involved in gene imprinting, and aberrant expression of CPT1A and CPT1C, regulators of fatty acid oxidation. Our study may pave the way to identify new markers that could be potentially useful for diagnosis and/or prognosis of glioblastoma.

  • Giant thrombosed intracavernous carotid artery aneurysm presenting as Tolosa-Hunt syndrome in a patient harboring a new pathogenic neurofibromatosis type 1 mutation: a case report and review of the literature.

    Publication Date: 20/01/2014 on Neuropsychiatric disease and treatment
    by Conforti R, Cirillo M, Marrone V, Galasso R, Capaldo G, Giugliano T, Scuotto A, Piluso G, Melone MA
    DOI: 10.2147/NDT.S49784

    Neurofibromatosis type 1 (NF1) is a relatively common single-gene disorder, and is caused by heterozygous mutations in the NF1 gene that result in a loss of activity or in a nonfunctional neurofibromin protein. Despite the common association of NF1 with neurocutaneous features, its pathology can extend to numerous tissues not derived from the neural crest. Among the rare cerebrovascular abnormalities in NF1, more than 85% of cases are of purely occlusive or stenotic nature, with intracranial aneurysm being uncommon. Predominantly, the aneurysms are located in the internal carotid arteries (ICAs), being very rare bilateral aneurysms. This report describes a very unusual case of fusiform aneurysms of both ICAs in a Caucasian NF1 patient, with a new pathogenic intragenic heterozygous deletion of the NF1 gene, presenting at age 22 years with Tolosa-Hunt syndrome, because of partial thrombosis of the left giant intracavernous aneurysm. Medical treatment with anticoagulant therapy allowed a good outcome for the patient. In conclusion, early identification of cerebral arteriopathy in NF1 and close follow-up of its progression by neuroimaging may lead to early medical or surgical intervention and prevention of significant neurologic complications.

  • Silencing of RB1 and RB2/P130 during adipogenesis of bone marrow stromal cells results in dysregulated differentiation.

    Publication Date: 01/01/2014 on Cell cycle (Georgetown, Tex.)
    by Capasso S, Alessio N, Di Bernardo G, Cipollaro M, Melone MA, Peluso G, Giordano A, Galderisi U
    DOI: 10.4161/cc.27275

    Bone marrow adipose tissue (BMAT) is different from fat found elsewhere in the body, and only recently have some of its functions been investigated. BMAT may regulate bone marrow stem cell niche and plays a role in energy storage and thermogenesis. BMAT may be involved also in obesity and osteoporosis onset. Given the paramount functions of BMAT, we decided to better clarify the human bone marrow adipogenesis by analyzing the role of the retinoblastoma gene family, which are key players in cell cycle regulation. Our data provide evidence that the inactivation of RB1 or RB2/P130 in uncommitted bone marrow stromal cells (BMSC) facilitates the first steps of adipogenesis. In cultures with silenced RB1 or RB2/P130, we observed an increase of clones with adipogenic potential and a higher percentage of cells accumulating lipid droplets. Nevertheless, the absence of RB1 or RB2/P130 impaired the terminal adipocyte differentiation and gave rise to dysregulated adipose cells, with alteration in lipid uptake and release. For the first time, we evidenced that RB2/P130 plays a role in bone marrow adipogenesis. Our data suggest that while the inactivation of retinoblastoma proteins may delay the onset of last cell division and allow more BMSC to be committed to adipocyte, it did not allow a permanent cell cycle exit, which is a prerequisite for adipocyte terminal maturation.

  • Systemic delivery of recombinant brain derived neurotrophic factor (BDNF) in the R6/2 mouse model of Huntington's disease.

    Publication Date: 20/05/2013 on PloS one
    by Giampà C, Montagna E, Dato C, Melone MA, Bernardi G, Fusco FR
    DOI: 10.1371/journal.pone.0064037

    Loss of huntingtin-mediated BDNF gene transcription has been shown to occur in HD and thus contribute to the degeneration of the striatum. Several studies have indicated that an increase in BDNF levels is associated with neuroprotection and amelioration of neurological signs in animal models of HD. In a recent study, an increase in BDNF mRNA and protein levels was recorded in mice administered recombinant BDNF peripherally. Chronic, indwelling osmotic mini-pumps containing either recombinant BDNF or saline were surgically placed in R6/2 or wild-type mice from 4 weeks of age until euthanasia. Neurological evaluation (paw clasping, rotarod performance, locomotor activity in an open field) was performed. After transcardial perfusion, histological and immunohistochemical studies were performed. We found that BDNF- treated R6/2 mice survived longer and displayed less severe signs of neurological dysfunction than the vehicle treated ones. Primary outcome measures such as brain volume, striatal atrophy, size and morphology of striatal neurons, neuronal intranuclear inclusions and microglial reaction confirmed a neuroprotective effect of the compound. BDNF was effective in increasing significantly the levels of activated CREB and of BDNF the striatal spiny neurons. Moreover, systemically administered BDNF increased the synthesis of BDNF as demonstrated by RT-PCR, and this might account for the beneficial effects observed in this model.

  • Phosphodiesterase 10A (PDE10A) localization in the R6/2 mouse model of Huntington's disease.

    Publication Date: 01/04/2013 on Neurobiology of disease
    by Leuti A, Laurenti D, Giampà C, Montagna E, Dato C, Anzilotti S, Melone MA, Bernardi G, Fusco FR
    DOI: 10.1016/j.nbd.2012.11.016

    In Huntington's disease (HD) mutant huntingtin protein impairs the function of several transcription factors, in particular the cAMP response element-binding protein (CREB). CREB activation can be increased by targeting phosphodiesterases such as phospohodiesterase 4 (PDE4) and phosphodiesterase 10A (PDE10A). Indeed, both PDE4 inhibition (DeMarch et al., 2008) and PDE10A inhibition (Giampà et al., 2010) proved beneficial in the R6/2 mouse model of HD. However, Hebb et al. (2004) reported PDE10A decline in R6/2 mice. These findings raise the issue of how PDE10A inhibition is beneficial in HD if such enzyme is lost. R6/2 mice and their wild type littermates were treated with the PDE10A inhibitor TP10 (a gift from Pfizer) or saline, sacrificed at 5, 9, and 13 weeks of age, and single and double label immunohistochemistry and western blotting were performed. PDE10A increased dramatically in the spiny neurons of R6/2 compared to the wild type mice. Conversely, in the striatal cholinergic interneurons, PDE10A was lower and it did not change significantly with disease progression. In the other subsets of striatal interneurons (namely, parvalbuminergic, somatostatinergic, and calretininergic interneurons) PDE10A immunoreactivity was higher in the R6/2 compared to the wild-type mice. In the TP10 treated R6/2, PDE10A levels were lower than in the saline treated mice in the medium spiny neurons, whereas they were higher in all subsets of striatal interneurons except for the cholinergic ones. However, in the whole striatum densitometry studies, PDE10A immunoreactivity was lower in the R6/2 compared to the wild-type mice. Our study demonstrates that PDE10A is increased in the spiny neurons of R6/2 mice striatum. Thus, the accumulation of PDE10A in the striatal projection neurons, by hydrolyzing greater amounts of cyclic nucleotides, is likely to contribute to cell damage in HD. Consequently, the beneficial effect of TP10 in HD models (Giampà et al., 2009, 2010) is explained by the efficiency of such compound in counteracting this phenomenon and therefore increasing the availability of cyclic nucleotides.

  • The ADAMTS18 gene is responsible for autosomal recessive early onset severe retinal dystrophy.

    Publication Date: 28/01/2013 on Orphanet journal of rare diseases
    by Peluso I, Conte I, Testa F, Dharmalingam G, Pizzo M, Collin RW, Meola N, Barbato S, Mutarelli M, Ziviello C, Barbarulo AM, Nigro V, Melone MA, , Simonelli F, Banfi S
    DOI: 10.1186/1750-1172-8-16

    Inherited retinal dystrophies, including Retinitis Pigmentosa and Leber Congenital Amaurosis among others, are a group of genetically heterogeneous disorders that lead to variable degrees of visual deficits. They can be caused by mutations in over 100 genes and there is evidence for the presence of as yet unidentified genes in a significant proportion of patients. We aimed at identifying a novel gene for an autosomal recessive form of early onset severe retinal dystrophy in a patient carrying no previously described mutations in known genes.

  • Efficient cultivation of neural stem cells with controlled delivery of FGF-2.

    Publication Date: 01/01/2013 on Stem cell research
    by Galderisi U, Peluso G, Di Bernardo G, Calarco A, D'Apolito M, Petillo O, Cipollaro M, Fusco FR, Melone MA
    DOI: 10.1016/j.scr.2012.09.001

    Neural stem cells (NSCs) raised the hope for cell-based therapies in human neurodevelopmental and neurodegenerative diseases. Current research strategies aim to isolate, enrich, and propagate homogeneous populations of neural stem cells. Unfortunately, several concerns with NSC cultures currently may limit their therapeutic promise. Exhaustion of growth factors and/or their uncontrolled release with burst and fall in their concentration may greatly affect the in vitro behavior of NSCs. In this context, we investigate whether a device containing heparan sulfate (HS), which is a co-factor in growth factor-mediated cell proliferation and differentiation, could potentiate and prolong the delivery of fibroblast growth factor-2 (FGF-2) and thus improve in vitro NSC cultivation. We demonstrated that NSCs cultivated in media with a controlled release of FGF-2 from a polyelectrolyte polymer showed a higher proliferation rate, and reduced apoptosis and senescence. In these experimental conditions NSCs preserve their stemness properties for a longer period of time compared with controls. Also of interest is that cell fate properties are conserved as well. The controlled release of FGF-2 reduced the level of oxidative stress and this is associated with a lower level of damaged DNA. This result may explain the reduced level of senescence and apoptosis in NSCs cultivated in the presence of hydrogel-releasing FGF-2.

  • Mutant huntingtin regulates EGF receptor fate in non-neuronal cells lacking wild-type protein.

    Publication Date: 01/01/2013 on Biochimica et biophysica acta
    by Melone MA, Calarco A, Petillo O, Margarucci S, Colucci-D'Amato L, Galderisi U, Koverech G, Peluso G
    DOI: 10.1016/j.bbadis.2012.09.001

    Huntingtin (htt) is a scaffold protein localized at the subcellular level and is involved in coordinating the activity of several protein for signaling and intracellular transport. The emerging properties of htt in intracellular trafficking prompted us to study the role of mutant htt (polyQ-htt) in the intracellular fate of epidermal growth factor receptor (EGFR), whose activity seems to be strictly regulated by htt. In particular, to evaluate whether protein trafficking dysfunction occurs in non-neuronal cells in the absence of functional htt, we monitored the EGFR protein in fibroblasts from homozygotic HD patients and their healthy counterpart. We found that polyQ-htt controls EGFR degradation and recycling. Lack of wild-type htt caused alteration of the ubiquitination cycle, formation of EGFR-incorporating high-molecular weight protein aggregates and abnormal EGFR distribution in endosomes of the degradation and recycling pathways after EGF stimulation. PolyQ-htt-induced alteration of EGFR trafficking affected cell migration and proliferation, at least in part, through inhibition of ERK signaling. To our knowledge the data here reported represent the first signaling and phenotypic characterization of polyQ-htt involvement in the modulation of growth factor stimulation in non-neuronal cells.