Member PUBLICATIONS

• Identification, Characterization, and Regulatory Mechanisms of a Novel EGR1 Splicing Isoform.

  Publication Date: 28/03/2019 on International journal of molecular sciences

  by Aliperti V, Sgueglia G, Aniello F, Vitale E, Fucci L, Donizetti A

  DOI: 10.3390/ijms20071548

  EGR1 is a transcription factor expressed in many cell types that regulates genes involved in different biological processes including growth, proliferation, and apoptosis. Dysregulation of EGR1 expression has been associated with many pathological conditions such as tumors and brain diseases. Known molecular mechanisms underlying the control of EGR1 function include regulation of transcription, mRNA and protein stability, and post-translational modifications. Here we describe the identification of a splicing isoform for the human gene. The newly identified splicing transcript encodes a shorter protein compared to the canonical EGR1. This isoform lacks a region belonging to the N-terminal activation domain and although it is capable of entering the nucleus, it is unable to activate transcription fully relative to the canonical isoform.

• Circulating levels of IL-1 family cytokines and receptors in Alzheimer's disease: new markers of disease progression?

  Publication Date: 12/12/2018 on Journal of neuroinflammation

  by Italiani P, Puxeddu I, Napoletano S, Scala E, Melillo D, Manocchio S, Angiolillo A, Migliorini P, Boraschi D, Vitale E, Di Costanzo A

  DOI: 10.1186/s12974-018-1376-1

  Although the mechanisms underlying AD neurodegeneration are not fully understood, it is now recognised that inflammation could play a crucial role in the initiation and progression of AD neurodegeneration. A neuro-inflammatory network, based on the anomalous activation of microglial cells, includes the production of a number of inflammatory cytokines both locally and systemically. These may serve as diagnostic markers or therapeutic targets for AD neurodegeneration.

• GRN deletion in familial frontotemporal dementia showing association with clinical variability in 3 familial cases.

  Publication Date: 01/05/2017 on Neurobiology of aging

  by Milan G, Napoletano S, Pappatà S, Gentile MT, Colucci-D'Amato L, Della Rocca G, Maciag A, Rossetti CP, Fucci L, Puca A, Grossi D, Postiglione A, Vitale E

  DOI: 10.1016/j.neurobiolaging.2016.12.030

  Progranulin (GRN) gene mutations have been genetically associated with frontotemporal dementia (FTD) and are present in about 23% of patients with familial FTD. However, the neurobiology of this secreted glycoprotein remains unclear. Here, we report the identification of 3 pedigrees of Southern Italian extraction in whom FTD segregates with autosomal dominant inheritance patterns. We present evidence that all the available patients in these 3 familial cases are carrying the rare GRN gene exon 6 deletion g10325_10331delCTGCTGT (relative to nt 1 inNG_007886.1), alias Cys157LysfsX97. This mutation was previously described in 2 sporadic cases but was never associated with familial cases. Our patients demonstrate heterogeneous clinical phenotypes, such as the behavioral variant (bvFTD) in the affected men and the nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA) in the affected woman. Haploinsufficiency was revealed by both quantitative real-time PCR of the gene and protein analyses. These findings provide further support for a previously proposed role for the GRN gene in the genetic etiology of FTD and its phenotypic variability.

• Imidazole-stabilized gold nanoparticles induce neuronal apoptosis: an in vitro and in vivo study.

  Publication Date: 01/04/2015 on Journal of biomedical materials research. Part A

  by Imperatore R, Carotenuto G, Di Grazia MA, Ferrandino I, Palomba L, Mariotti R, Vitale E, De Nicola S, Longo A, Cristino L

  DOI: 10.1002/jbm.a.35289

  Gold nanoparticles are increasingly being employed in innovative biological applications thanks to their advantages of material- and size-dependent physics and chemical interactions with the cellular systems. On the other hand, growing concern has emerged on the toxicity which would render gold-based nanoparticles harmful to cell cultures, animals, and humans. Emerging attention is focused on the interaction of gold nanoparticles with nervous system, especially regarding the ability to overcome the blood-brain barrier (BBB) which represents the major impediment to the delivery of therapeutics into the brain. We synthesized highly stable 2-mercapto-1-methylimidazole-stabilized gold-nanoparticles (AuNPs)-mmi to investigate their entry, accumulation, and toxicity in vitro (SH-SY5Y human neuroblastoma cells) and in vivo (brain of C57BL/6 mice) through optical and electron microscopy. After incubation in the cell culture medium at the lowest dose of 0.1 mg/mL the (AuNPs)-mmi nanoparticles were found compacted and recruited into endosome/lysosomes (1 h) before their fusion (2 h) and the onset of neuronal death by apoptosis (4 h) as proved by terminal-transferase-mediated dUTP nick end labeling assay and caspase-3 immunoreactivity. The ability of (AuNPs)-mmi to cross the BBB was assessed by injection in the caudal vein of C57BL/6 mice. Among different brain regions, the nanoparticles were found in the CaudatoPutamen area, mainly in the striatal neurons 4 h after injection. These neurons showed the typical hallmarks of apoptosis. Our findings provide, for the first time, the dynamic of 2-mercapto-1-methylimidazole nanogold uptake. The molecular mechanism which underlies the nanogold-driven apoptotic event is analyzed and discussed in order to take into account when designing nanomaterials to interface with biological structures.

• Role of cytosolic calcium-dependent phospholipase A2 in Alzheimer's disease pathogenesis.

  Publication Date: 01/06/2012 on Molecular neurobiology

  by Gentile MT, Reccia MG, Sorrentino PP, Vitale E, Sorrentino G, Puca AA, Colucci-D'Amato L

  DOI: 10.1007/s12035-012-8279-4

  Phospholipases (PLA2s) are a superfamily of enzymes characterized by the ability to specifically hydrolyze the sn-2 ester bond of phospholipids generating arachidonic acid, utilized in inflammatory responses, and lysophospholipids involved in the control of cell membrane remodeling and fluidity. PLA2s have been so far considered a crucial element in the etiopathogenesis of several neurological diseases such as cerebral ischemia, multiple sclerosis, Parkinson's disease, and Alzheimer's disease (AD). In AD, the role of beta-amyloid (Aβ) fragments is well established although still more elusive are the molecular events of the cascade that from the Aβ accumulation leads to neurodegeneration with its clinical manifestations. However, it is well known that inflammation and alteration of lipid metabolism are common features of AD brains. Findings obtained from in vitro studies, animal models, and human brain imaging analysis point towards cPLA2 as a key molecule in the onset and maintenance of the neurodegenerative mechanism(s) of AD. In this review, we have focused on the molecular and biological evidence of the involvement of cPLA2s in the pathogenesis of AD. An insight into the molecular mechanism(s) underlying the action and the regulation of cPLA2 is of tremendous interest in the pharmaceutical and biotechnology industry in developing selective and potent inhibitors able to modulate the onset and/or the outcome of AD.

• Highly variable penetrance in subjects affected with cavernous cerebral angiomas (CCM) carrying novel CCM1 and CCM2 mutations.

  Publication Date: 05/07/2007 on American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

  by Gianfrancesco F, Cannella M, Martino T, Maglione V, Esposito T, Innocenzi G, Vitale E, Liquori CL, Marchuk DA, Squitieri F

  DOI: 10.1002/ajmg.b.30381

  Cavernous vascular malformations may affect brain and out-of-brain tissues. In most cases, cerebral cavernous malformations (CCMs) involve the brain alone, and are rarely associated with skin hemangiomas, spinal cord, retinal, hepatic or vertebral lesions. CCMs can cause seizures, intracranial and spinal haemorrhages, focal neurological deficits, and migraine-like headaches. After collecting CCM families of Italian origin and investigating the genetic basis of the disorder we disclosed two novel molecular variations in the KRIT1 and MGC4607 genes. We found a novel CCM1 gene mutation (Q66X) in a family with apparently asymptomatic old-aged mutation carriers and patients who either had skin angiomas alone or the full association of cerebral, spinal, and skin lesions. In this family we report the highest variability in mutation penetrance so far described, including the presence of CCM in one subject since birth (surgery at 19 months of age), a condition to our knowledge so far unreported. In a CCM2 affected family, we also report a novel causative mutation, (54_55delAC) in exon 2 of the MGC4607 gene, that produces a truncated protein containing only 22 amino acids. These data describe novel CCM mutations associated with a particularly high variability of the penetrance causing, in some cases, reduced expression of clinical symptoms and sporadic cases with apparent negative family history. Hence they emphasize the importance of DNA-based diagnostics and genetic counseling to identify unaffected mutation carriers subjects, even at advanced age.