?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.title=IGS-2.7%3A+un+nuevo+inhibidor+de+la+Case%C3%ADna+quinasa-1%CE%B4+para+el+tratamiento+de+la+ELA&rft.creator=Bueso+de+Barrio%2C+Jes%C3%BAs+Alejandro&rft.contributor=Mart%C3%ADn+Requero%2C+Mar%C3%ADa+%C3%81ngeles&rft.contributor=Carri%C3%B3+Gonz%C3%A1lez%2C+Elena&rft.subject=Biology&rft.subject=Medicine&rft.description=Amyotrophic+lateral+sclerosis+(ALS)+is+a+neurodegenerative+disease+which+is+characterized+by+a+progressive+muscular+paralysis+due+to+upper+and+lower+motoneurons+degeneration.+Even+though+it+currently+has+no+curative+treatment%2C+there+are+two+approved+symptomatic+treatments+for+the+disease%2C+being+those+Riluzole+and+Edaravone.+The+diagnosis+is+difficult+since+it+depends+on+the+disease+progression.+However%2C+there+are+some+criteria+to+help+with+the+diagnoses.+Over+90%25+of+the+cases+develope+a+TDP-43+(transactive+response+DNA+binding+protein+43+kDa)+protein+pathology+related+to+the+hyperphosphorylation+and+ubiquitination+of+the+protein+along+with+protein+mislocalization%2C+leading+to+an+abnormal+aggregation+in+the+cytoplasm.+The+main+kinase+involved+in+TDP-43+hyperphosphorylation+is+CK-1%CE%B4+(casein+kinase+1+isoform+%CE%B4).+However%2C+there+is+no+evidence+of+TDP-43+proteinopathology+in+patients+with+mutated+SOD1+(superoxide+dismutase+1)+gene+(SOD1-ALS)%2C+who+show+SOD1+protein+aggregates+rather+than+TDP-43+aggregates.+Being+a+multisystemic+disease+makes+it+complicated+to+find+reliable+models+to+study+the+disease.+The+use+of+lymphoblastoid+cell+lines+(LCLs)+in+this+project+will+aim+to+prove+the+validity+of+these+cells+as+a+model+of+physiopathological+study.+These+LCLs+have+been+obtained+from+sporadic+ALS+(sALS)+and+SOD1-ALS+patients+blood.+The+effects+on+cellular+functions+in+response+to+a+CK-1%CE%B4+inhibitor+(IGS-2.7)+will+be+analyzed+throughout+the+project.+The+capability+of+IGS-2.7+to+restore+TDP-43+homeostasis+will+also+be+studied.+The+expression+of+phosphorylated+TDP-43+was+evaluated+on+sALS+and+SOD1-ALS+LCLs+by+western+blot.+TDP-43+mislocalization+was+observed+on+sALS+LCLs+using+confocal+laser+scanning+microscopy.+The+cellular+functions+were+analyzed+via+different+studies%2C+including+viability+assays%2C+oxygen+consumption+rate%2C+extracellular+acidification+rate+and+metabolism+studies.+The+results+show+that+the+LCLs+are+an+adequate+experimental+model+since+they+recapitulate+the+main+alterations+which+have+been+observed+in+affected+motoneurons.+LCLs+from+sALS+patients+display+a+significantly+increased+phosphorylation+of+TDP-43.+The+treatment+of+LCLs+with+IGS-2.7+does+not+significantly+alter+cell+viability+nor+metabolism+but+it+normalizes+the+phosphorylation+state+of+TDP-43+and+prevents+its+mislocalization+on+treated+sALS+LCLs.+Additionally%2C+the+treatment+with+IGS-2.7+restores+the+decreased+reserve+respiratory+capacity+of+both+sALS+and+SOD1-ALS+LCLs.&rft.publisher=E.T.S.+de+Ingenier%C3%83%C2%ADa+Agron%C3%83%C2%B3mica%2C+Alimentaria+y+de+Biosistemas+(UPM)&rft.rights=http%3A%2F%2Fcreativecommons.org%2Flicenses%2Fby-nc-nd%2F3.0%2Fes%2F&rft.date=2020-06&rft.type=info%3Aeu-repo%2Fsemantics%2FbachelorThesis&rft.type=Final+Project&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=spa&rft.rights=info%3Aeu-repo%2Fsemantics%2FopenAccess&rft.identifier=http%3A%2F%2Foa.upm.es%2F65754%2F