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Cooperability
| Project leader |
Hecimovic Silva |
| Project co-leader: |
Dimitri Krainc |
| Administering organization: |
Rudjer Boskovic Institute, Bijenicka c. 54, 10000 Zagreb, Croatia, www.irb.hr, OIB 69715301002, Marijana Klasnic Kozar, Phone: +385-1-4571342, Email: Marijana.Klasnic.Kozar@irb.hr |
| Partner Institution/Company: |
Northwestern University Feinberg School of Medicine |
| Grant type: |
1B |
| Project title: |
Lysosomal dysfunction as a common mechanism of neurodegenerative diseases |
| Project summary: |
Lysosomes are specific cellular organelles that are normally involved in degradation processes of proteins and other damaged organelles. Dysfunction of lysosomes may lead to abnormal protein accumulation which may cause cell degeneration and death. Such protein accumulation also occurs in the brain cells and triggers development of the devastating neurodegenerative diseases in humans, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Although AD and PD are the most common neurodegenerative diseases, there are still no adequate therapies that would prevent or cure AD and PD. In addition, the underlying cellular processes which lead to AD and PD are still not completely understood. In this project we will employ our knowledge and use modern and sophisticated technologies to unravel a molecular mechanism that leads to AD and PD in order to develop targeted and effective future therapies. Recent studies suggest that dysregulation of lysosomes may result in protein accumulation and neurodegeneration. Additionally, it is intriguing that several human rare inherited disorders caused by dysfunction of the lysosomal proteins, such as Niemann-Pick type C disease (NPC), show neurodegeneration and accumulation of proteins characteristic for AD and PD. Although these findings provide a further evidence for the link between lysosomal dysfunction, protein accumulation and neurodegenerative processes, molecular details of this relationship are largely unknown. Using a lysosomal disorder NPC as a model, the goal of this project is to investigate a role of lysosomal impairment on accumulation of amyloid-beta peptide (Abeta) and alpha-synuclein (a-syn), the two characteristic features in the pathogenesis of AD and PD. We will employ pharmacological treatments and genetic approaches to analyze whether enhancement or inhibition of the lysosomal function can rescue accumulation of Abeta/a-syn and whether their lysosomal clearance may attenuate neurotoxicity and neuronal degeneration. In addition, we will use state-of-the-art induced pluripotent stem cell technology to generate human NPC neurons by reprogramming the NPC patients’ fibroblasts. The human NPC neurons will be used to validate the relevant targets that are involved in lysosomal function, accumulation of Abeta/a-syn and neurodegeneration. This project will generate new ideas for an effective and highly specific therapy against neurodegenerative diseases, including AD and PD. Our results may provide evidence that lysosomal dysfunction is a common mechanism that leads to neurodegeneration and may lead to development of a novel therapeutic strategy against neurodegenerative disorders. |
| Hrvatski sažetak: |
Lizosomi su specifične stanične organele u kojima se odvija razgradnja nefunkcionalnih proteina ili oštećenih staničnih dijelova. Poremećena funkcija lizosoma može dovesti do nakupljanja proteina te uzrokovati degeneraciju stanica i njihovo odumiranje. Takvo nakupljanje proteina događa se u mozgu, što kao posljedicu može imati nastanak teških neurodegenerativnih bolesti u čovjeka, kao što su Alzheimerova bolest (AB) i Parkinsonova bolest (PB). Iako AB i PB spadaju u najčešće neurodegenerativne bolesti, još uvijek za njih ne postoji adekvatna terapija, kojom bi se spriječila ili izliječila AB i PB. Također, nisu potpuno poznati stanični procesi koji uzrokuju nastanak ovih bolesti. Ovim projektom želimo upotrijebiti naša znanja i suvremenu, sofisticiranu tehnologiju kako bismo otkrili molekularni mehanizam koji dovodi do nastanka AB i PB s ciljem razvoja specifične i učinkovite terapije. Nedavna istraživanja sugeriraju da bi disfunkcija lizosoma mogla rezultirati nakupljanjem proteina i neurodegeneracijom. Osim toga, intrigantno je da nekoliko rijetkih nasljednih bolesti u čovjeka koje su uzrokovane disfunkcijom lizosomalnih proteina, kao što je bolest Nieman-Pick tipa C (NPC), pokazuje neurodegeneraciju i nakupljanje proteina karakterističnih za AB i PB. Iako ovi nalazi dodatno potvrđuju povezanost poremećene funkcije lizosoma, nakupljanja proteina i neurodegenerativnih procesa, molekularni detalji ove veze još uvijek nisu razjašnjeni. Koristeći stanični model lizosomalne bolesti NPC cilj ovog projekta je ispitati ulogu lizosoma i njihove disfunkcije na nakupljanje peptida amiloid-beta (Abeta) i alfa-sinukleina (a-syn), dva ključna proteina u patogenezi Alzheimerove, odnosno Parkinsonove bolesti. Farmakološkim tretmanima i genetičkim manipulacijama istražit ćemo može li stimulacija ili inhibicija funkcije lizosoma doprinijeti uklanjanju nakupina proteina Abeta/a-syn te može li njihova razgradnja u lizosomima umanjiti neurotoksičnost i odumiranje neurona. Osim toga, primjenom state-of-the-art tehnologije induciranih pluripotentnih matičnih stanica i reprogramiranjem fibroblasta pacijenata s NPC razvit ćemo humani model stanica neurona NPC. Humane neurone NPC ćemo koristiti kako bismo potvrdili biološki relevantne čimbenike odgovorne za (dis)funkciju lizosoma, nakupljanje proteina Abeta/a-syn i neurodegeneraciju. Ovaj projekt će doprinijeti razvoju novih ideja za učinkovitu i visoko specifičnu terapiju neurodegenerativnih bolesti, kao što su AB i PB. Rezultati ovog projekta bi mogli ukazati na disfunkciju lizosoma kao jedinstvenog mehanizma odgovornog za pojavu neurodegeneracije i dovesti do razvoja novog pristupa liječenju neurodegenerativnih bolesti. |
| Amount requested from UKF: |
1.463.294,12 HRK |
| Amount of matching funding: |
292.658,84 HRK |
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