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Young Researchers and Professionals
| Project leader |
Borovecki Fran |
| Project co-leader: |
Tiago Fleming Outeiro |
| Administering organization: |
Center for Functional Genomics, Zagreb Medical School, University of Zagreb, Šalata 3b, 10000 Zagreb, Croatia, www.mef.hr
Prof. Nada Cikes, MD, PhD, Dean
Tel: +385-1-4815132
Mail: fbor@mef.hr
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| Partner Institution/Company: |
Institute for Molecular Medicine, University of Lisbon |
| Grant type: |
3A |
| Project title: |
Location analysis of alpha-synuclein promoter binding in Parkinson’s disease |
| Project summary: |
Possible mechanisms of transcriptional deregulation have thus far been studied extensively in multiple models of neurodegenerative diseases. Although majority of the work has been carried out in the field of polyglutamine-expansion diseases, such as Huntington’s disease, molecular mechanisms of transcriptional deregulation have recently become a focus in Parkinson’s disease (PD) as well. PD is the most common disorder of movement, affecting at least 3% of the population over the age of 65 years. The characteristic motor features are development of a rest tremor, bradykinesia, rigidity, and impairment of postural balance. Current therapy of PD is based primarily on augmentation or replacement of dopamine, using the biosynthetic precursor levodopa or other drugs which activate dopamine receptors. Abnormal folding and aggregation of proteins in the central nervous system appears to be a common mechanism of neurodegenerative disease, including trinucleotide repeat disorders, Alzheimer’s disease, and Parkinson’s disease. In Parkinson’s disease, neuronal accumulation of aggregated ?-synuclein has been proposed to be centrally involved in the pathophysiology because mutations in the ?-synuclein gene (A30O, E46K, and A53T) are associated with rare familial forms of Parkinson’s disease, and ?-synuclein is abundant in Lewy bodies even in sporadic Parkinson’s disease. The overall objective of the project is to assess possible mechanisms of transcriptional deregulation in models of Parkinson’s disease by studying differential promoter recruitment by ?-synuclein. To this end chromatin immunoprecipitation on CHIP approach will be used. Identification of possible target promoters for ?-synuclein may reveal novel mechanisms of neurodegeneration involved in development and progression of PD. Furthermore, within the proposed project we also plan to implement some of the findings by using luciferase tagged constructs of promoters shown to be most significantly decreased in expression upon binding of ?-synuclein in an effort to develop possible primary assays which may be used in high-throughput screening experiments. The present project aims at unveiling the role of ?-synuclein in the nucleus and its potential effect on transcription, which will yield novel clues into the pathways involved in neurotoxicity. Thus, we expect this project will open novel avenues for therapeutic intervention by identifying novel markers and targets. |
| Hrvatski sažetak: |
Mogući mehanizmi transkripcijske deregulacije do sada su ekstenzivno istraživani u različitim modelima neurodegenerativnih bolesti. Premda je većina istraživanja provođena na području bolesti uzrokovanih ekspanzijom poliglutaminskih ponavljanja, poput Huntingtonove bolesti, molekularni mehanizmi transkripcijske deregulacije postali su iznimno zanimljivi i u istraživanjima Parkinsonove bolesti (PB). PB je najčešća bolest motoričkih poremećaja, te zahvaća najmanje 3% populacije starije od 65 godina. Karakteristične motoričke smetnje su razvoj tremora u mirovanju, bradikinezija, ukočenost i nemogućnost održavanja posturalne ravnoteže. Trenutačna terapija za PB temelji se prvenstveno na povećavanju razine dopamina, korištenjem biosintetičkog prekursora levodope ili drugih lijekova koji aktiviraju dopaminske receptore. Abnormalna struktura i agregacija proteina u središnjem živčanom sustavu vjerojatni je zajednički mehanizam nastanka neurodegenerativnih bolesti, uključujući bolesti ponavljanja trinukleotida, Alzheimerovu i Parkinsonovu bolest. U PB nakupljanje alfa-sinuklein u živčanim stanicama jedno je od centralnih patofizioloških događaja, budući da su mutacije u genu za alfa-sinuklein (A300, E46K i A53T) povezane s rijetkim nasljednim oblicima PB, te budući da se alfa-sinuklein nalazi u obilju u Lewy tjelešcima čak i u sporadičnim oblicima PB. Glavni cilj predloženog projekta jest ispitati moguće mehanizme transkripcijske deregulacije u modelima PB pomoću istraživanja diferencijalnog regrutiranja promotora od strane alfa-sinukleina. Stoga ćemo provesti pokuse kromatinske imunoprecipitacije kombinirane s genskim čipovima. Identifikacija mogućih ciljnih promotora za alfa-sinuklein mogla bi otkriti nove mehanizme neurodegeneracije uključene u razvoj i progresiju PB. Nadalje, temeljem rezultata istraživanja odrediti ćemo promotore s najznačajnijim vezivanjem alfa-sinukleina, te ćemo pokušati razviti moguće primarne eseje za visoko-propusno probiranje novih lijekova za PB izradom promotor-luciferaza konstrukata. Predloženi projekt za cilj ima pojasniti ulogu alfa-sinukleina u jezgri, te njegov mogući učinak na transkripciju, što bi moglo otkriti nove spoznaje o signalnim putovima uključenim u procese neurotoksičnosti. Stoga očekujemo da će predloženi projekt otvoriti nove pravce za razvoj lijekova identificiranjem novih biljega i ciljnih mehanizama. |
| Amount requested from UKF: |
48.000 € |
| Amount of matching funding: |
12.000 € |
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