A5039055702- Wnt/β-catenin signaling in development and cancer
- Genetic Neurodegenerative Diseases
- Cancer-related gene regulation
- RNA Research and Splicing
- Mitochondrial Function and Pathology
- Neuroscience and Neuropharmacology Research
- Muscle Physiology and Disorders
- Genetics and Neurodevelopmental Disorders
- Nuclear Receptors and Signaling
- RNA modifications and cancer
- Renal and related cancers
- Neurological disorders and treatments
- Alzheimer's disease research and treatments
- Computational Drug Discovery Methods
- Kruppel-like factors research
- MicroRNA in disease regulation
- Epigenetics and DNA Methylation
- TGF-β signaling in diseases
- Cholinesterase and Neurodegenerative Diseases
- Cell death mechanisms and regulation
- Glycosylation and Glycoproteins Research
- Parkinson's Disease Mechanisms and Treatments
- Iron Metabolism and Disorders
- Trace Elements in Health
- Fungal and yeast genetics research
Kedrion (Italy)
2021-2025
IRBM Science Park
2014-2023
Alzheimer’s Research UK
2017-2018
University of Cambridge
2017-2018
Siena Biotech (Italy)
2006-2015
Agency for Science, Technology and Research
2013
Experimental Drug Development Centre
2013
London School of Hygiene & Tropical Medicine
2012
Sapienza University of Rome
2002-2004
University of Siena
2003-2004
We used primary cultures of cortical neurons to examine the relationship between beta-amyloid toxicity and hyperphosphorylation tau protein, biochemical substrate for neurofibrillary tangles Alzheimer's brain. Exposure peptide (betaAP) induced expression secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates canonical Wnt signaling pathway, thus activating tau-phosphorylating enzyme glycogen synthase kinase-3beta. was at late times after betaAP exposure, its dependent on tumor...
The Wilms tumor suppressor gene WT1 is implicated in the ontogeny of genito-urinary abnormalities, including Denys-Drash syndrome and kidney. encodes Kruppel-type zinc finger proteins that can regulate expression several growth-related genes, apparently by binding to specific DNA sites located within 5' untranslated leader regions as well promoter sequences. Both a closely related early growth response factor, EGR1, bind same sequences from mouse encoding insulin-like factor 2 (Igf-2). We...
To investigate the role of Wnt inhibitor Dickkopf-1 (DKK-1) in pathophysiology neurodegenerative diseases, we analysed DKK-1 expression and localization transgenic mouse models expressing familial Alzheimer's disease mutations a frontotemporal dementia mutation. A significant increase was found diseased brain areas all lines, where it co-localized with hyperphosphorylated tau-bearing neurons. In TgCRND8 mice, immunoreactivity detected neurons surrounding amyloid deposits within choline...
Protein acetylation, which is central to transcriptional control as well other cellular processes, disrupted in Huntington's disease (HD). Treatments that restore global acetylation levels, such inhibiting histone deacetylases (HDACs), are effective suppressing HD pathology model organisms. However, agents selectively target the disease-relevant HDACs have not been available. SirT1 (Sir2 Drosophila melanogaster) deacetylates histones and proteins including transcription factors. Genetically...
Abstract We used cultured cerebellar granule cells to examine whether native group‐III metabotropic glutamate (mGlu) receptors are coupled the mitogen‐activated protein kinase (MAPK) and phosphatidylinositol‐3‐kinase (PI‐3‐K) pathways. Cultured responded mGlu receptor agonist, L ‐2‐amino‐4‐phosphonobutanoate ( l ‐AP4), with an increased phosphorylation activity of MAPKs (ERK‐1 ‐2) PI‐3‐K target, B (PKB/AKT). These effects were attenuated by antagonists, α‐methyl‐serine‐ O ‐phosphate (MSOP)...
WNT factors represent key mediators of many processes in animal development and homeostasis act through a receptor complex comprised members the Frizzled low density lipoprotein-related receptors (LRP). In mammals, 19 genes encoding Wingless Int-related factor (WNTs), 10 Frizzled, 2 LRP proteins have been identified, but little is known identities individual Frizzled-LRP combinations mediating effects specific factors. Additionally, several secreted modulators signaling including at least...
Expression of Dickkopf-1 (Dkk-1), a secreted protein that negatively modulates the Wnt pathway, was induced in hippocampus gerbils and rats subjected to transient global cerebral ischemia as well cultured cortical neurons challenged with an excitotoxic pulse. In ischemic animals, temporal regional pattern Dkk-1 expression correlated profile neuronal death, assessed by Nissl staining immunostaining adjacent hippocampal sections. Treatment animals either antisense oligonucleotides or lithium...
Inhibition of the canonical Wnt pathway has been implicated in pathophysiology neuronal death. Here, we report that secreted antagonist, Dickkopf-1 (Dkk-1) is rapidly induced neurons after induction focal brain ischemia. In rats undergoing transient ischemia response to infusion endothelin-1, Dkk-1 was ischemic core and penumbra region. Induction associated with a reduced expression beta-catenin (a downstream signaling molecule pathway), not observed expressing protective protein, heat shock...
Although Huntington's disease is caused by the expansion of a CAG triplet repeat within context 3144-amino acid huntingtin protein (HTT), studies reveal that N-terminal fragments HTT containing expanded PolyQ region can be produced proteolytic processing and/or aberrant splicing. are also prevalent in postmortem tissue, and expression some these model organisms cause pathology. This has led to hypothesis peptides may critical modulators pathology, raising possibility targeting splicing or...
Significance The findings in this manuscript report on the identification of a posttranslational modification huntingtin protein (phosphorylation residue T3 N17 region protein), which can revert conformational effects Huntington’s disease (HD) mutation itself and inhibit its aggregation properties vitro. Using first ultrasensitive immunoassay for protein, we demonstrate that pT3 levels are decreased mutant preclinical models as well clinically relevant samples from HD patients. These high...
L-Acetylcarnitine (LAC, 100 mg/kg, s.c.), a drug commonly used for the treatment of painful neuropathies, substantially reduced mechanical allodynia in rats subjected to monolateral chronic constriction injury (CCI) sciatic nerve and also attenuated acute thermal pain intact rats. In both cases, induction analgesia required repeated injections LAC, suggesting that induces plastic changes within nociceptive pathway. CCI- sham-operated rats, 24-day with LAC increased expression metabotropic...
Summary: Inhibition of the Wnt pathway by secreted glycoprotein, Dickkopf‐1 (Dkk‐1) has been related to processes excitotoxic and ischemic neuronal death. We now report that Dkk‐1 is induced in neurons rat olfactory cortex hippocampus degenerating response seizures produced systemic injection kainate (12 mg/kg, i.p.). There was a tight correlation between expression death both regions, as shown different profiles animals classified “high” “low” responders kainate. For example, no induction...
We examined the effect of three human isoforms apolipoprotein E (ApoE2, ApoE3, and ApoE4) on canonical Wnt signaling pathway in undifferentiated PC12 cells. Addition recombinant ApoE4 reduced Wingless-Int7a-stimulated gene expression at concentrations 80 500 nm. Recombinant ApoE2 ApoE3 were virtually inactive. also inhibited when combined with very low density lipoproteins (VLDLs) or cells over-expressing lipoprotein receptor-related protein, LRP6. In contrast, enforced LRP5 unmasked an...
Phosphorylation of the N-terminal domain huntingtin (HTT) protein has emerged as an important regulator its localization, structure, aggregation, clearance and toxicity.However, validation effect bona fide phosphorylation in vivo assessing therapeutic potential targeting for treatment Huntington's disease (HD) require identification enzymes that regulate HTT phosphorylation.Herein, we report discovery a kinase, TANK-binding kinase 1 (TBK1), efficiently phosphorylates full-length fragments...
A disintegrine and metalloproteinase 10 (ADAM10) is implicated in synaptic function through its interaction with postsynaptic receptors adhesion molecules. Here, we report that levels of active ADAM10 are increased Huntington's disease (HD) mouse cortices striata human postmortem caudate. We show that, the presence polyglutamine-expanded (polyQ-expanded) huntingtin (HTT), accumulates at densities (PSDs) causes excessive cleavage protein N-cadherin (N-CAD). This aberrant phenotype also...
Abstract Plasma-derived therapeutic proteins are produced through an industrial fractionation process where purified from individual intermediates, some of which remain unused and discarded. Relatively few plasma-derived exploited clinically, with most available plasma being directed towards the manufacture immunoglobulin albumin. Although proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, high cost together small patient...
We have shown that cortical neurons challenged with toxic concentrations of beta-amyloid peptide (betaAP) enter the S phase cell cycle before apoptotic death. Searching for a signaling molecule lies at border between proliferation and death, we focused on disialoganglioside GD3. Exposure rat cultured to 25 microm betaAP(25-35) induced substantial increase in intracellular levels GD3 after 4 hr, time precedes neuronal entry into phase. decreased but still remained higher than control cultures...
Glioblastoma multiforme (GBM) is the most common and prognostically unfavorable form of brain tumor. The aggressive highly invasive phenotype these tumors makes them among anatomically damaging human cancers with a median survival less than 1 year. Although canonical Wnt pathway activation in has been historically linked to presence mutations involving key components (APC, β-catenin, or Axin proteins), an increasing number studies suggest that elevated signaling GBM initiated by several...