Genetski mehanizmi lizosomalne disfunkcije u Parkinsonovoj bolesti

Opis projekta
Accumulation of misfolded proteins in the brain represents a pathological hallmark of neurodegenerative diseases, suggesting that inadequate clearance of aggregation-prone proteins plays an important role in the disease pathogenesis. The synucleinopathies, including Parkinson’s disease (PD) and dementia with Lewy bodies (LBD), are a group of neurodegenerative disorders characterized by the accumulation and aggregation of a-synuclein (aSyn). Studies on the rare inherited forms of PD caused by mutations in the aSyn gene have highlighted disturbed aSyn clearance through the autophagy-lysosomal pathway (ALP) as a key mechanism leading to PD/LBD. Furthermore, several rare inherited disorders caused by mutations in the lysosomal genes show parkinsonian-like phenotype and accumulation of aSyn, providing additional evidence for the role of lysosomal dysfunction in the pathogenesis of synucleinopathies. The goal of the project is to elucidate the involvement of lysosomal gene mutations and lysosomal dysfunction in the ethiology of PD/LBD. Using the next-generation sequencing and Haloplex-based protocol we will design LYSOGENE platform to anayze genetic mutations/variations in the ALP genes that may lead to and predispose to PD/LBD. The identified ALP mutations will be further characterized in vitro in human neuronal cell lines using the knockdown and overexpression approaches. In particular, we will monitor how the identified mutations affect ALP function, accumulation and aggregation of aSyn, as well as neurotoxicity. Finally, we will validate our mechanistic findings in a biologically relevant model of human dopaminergic neurons derived from the PD/LBD patient’s fibroblasts using the induced pluripotent stem cell technology. Through these studies we will identify genetic variations/mutations in the ALP genes that cause or contribute to PD/LBD. The results of the project may help to identify potential new therapeutic targets for development of neuroprotective treatments.

Akronim
LYSOGENE PD

Šifra projekta
IP-2013-11-9386

Poziv
2013-11

Vrsta projekta
Znanstveno-istraživački

Vrsta financiranja
Kompetitivno projektno financiranje

Financijer
HRZZ - Hrvatska zaklada za znanost

Detalji financiranja
 IP - Istraživački projekti

Ukupan iznos financiranja projekta
997.709,00 HRK

Trajanje projekta
15-07-2014 - 14-07-2018

Ustanova - uloga
Medicinski fakultet, Zagreb - Nositelj (997.709,00 HRK) [15-07-2014 - 14-07-2018]

Osoba - Ustanova - uloga [pocetak - zavrsetak]
Fran Borovečki (MBZ: 230266, CROSBI: 17072) - Medicinski fakultet, Zagreb - Voditelj projekta [15-07-2014 - 14-07-2018]