title: Abnormal cell-clearance and accumulation of autophagic vesicles in lymphocytes from patients affected with Ataxia-Teleangiectasia.
abstract: Ataxia-Teleangiectasia (A-T) is a neurodegenerative disorder due to mutations in ATM gene. ATM in the nucleus ensures DNA repair, while its role in the cytosol is still poorly clarified. Abnormal autophagy has been documented in other neurodegenerative disorders, thus we evaluated whether alteration in this process may be involved in the pathogenesis of A-T by analyzing the autophagic vesicles and the genes implicated in the different stages of autophagy. Through transmission electron microscopy (TEM) and immunofluorescence analysis we observed an accumulation of APs associated with a LC3 puncta pattern, and a reduced number of ALs. We also documented an increased expression of genes involved in AP and lysosome biogenesis and function, and a decrease of Vps18 expression, involved in their vesicular trafficking and fusion. mTORC1-controlled proteins were hyperphosphorylated in A-T, in keeping with an increased mTOR inhibitory influence of autophagy. Betamethasone is able to promote the degradation of SQSTM1, a biomarker of autophagy. Collectively, our results indicate that in cells from A-T patients, the APs maturation is active, while the fusion between APs and lysosomes is inappropriate, thus implying abnormalities in the cell-clearance process. We also documented a positive effect of Betamethasone on molecules implicated in autophagosome degradation.
authors.affiliation: Department of Translational Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: D'Assante
authors.affiliation: Department of Translational Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fusco
authors.affiliation: Department of Translational Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Palamaro
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Polishchuk
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
authors.forename: Roman
authors.initials: R
authors.lastname: Polishchuk
authors.affiliation: Laboratory of Clinical Research and Advanced Diagnostics, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Bianchino
authors.affiliation: Laboratory of Clinical Research and Advanced Diagnostics, IRCCS Referral Cancer Center of Basilicata, Rionero in Vulture, Potenza, Italy.
authors.forename: Vitina
authors.initials: V
authors.lastname: Grieco
authors.affiliation: Department of Translational Medical Sciences, Federico II University, Naples, Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Prencipe
authors.affiliation: Department of Translational Medical Sciences, Federico II University, Naples, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.affiliation: Department of Translational Medical Sciences, Federico II University, Naples, Italy. Electronic address: pignata@unina.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pignata
mesh_terms: D001259:Ataxia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D001623:Betamethasone / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D015415:Biomarkers; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D001623:Betamethasone; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Ataxia-Teleangiectasia; Autophagosome-lysosome fusion; Autophagosomes; Autophagy; Cell-clearance