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doctoral thesis
Utjecaj unutarstaničnoga kolesterola i C-terminalnoga odsječka proteina prekursora amiloida β na funkciju retromera u modelima Alzheimerove bolesti
Zagreb: University of Zagreb, School of Medicine, 2020. urn:nbn:hr:105:191606
Dominko, Kristina
University of Zagreb
School of Medicine
Croatian Institiute for Brain Research

Institutional repository: Dr Med - University of Zagreb School of Medicine Digital Repository

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Dominko, K. (2020). Utjecaj unutarstaničnoga kolesterola i C-terminalnoga odsječka proteina prekursora amiloida β na funkciju retromera u modelima Alzheimerove bolesti (Doctoral thesis). Zagreb: University of Zagreb, School of Medicine. Retrieved from https://urn.nsk.hr/urn:nbn:hr:105:191606

Dominko, Kristina. "Utjecaj unutarstaničnoga kolesterola i C-terminalnoga odsječka proteina prekursora amiloida β na funkciju retromera u modelima Alzheimerove bolesti." Doctoral thesis, University of Zagreb, School of Medicine, 2020. https://urn.nsk.hr/urn:nbn:hr:105:191606

Dominko, Kristina. "Utjecaj unutarstaničnoga kolesterola i C-terminalnoga odsječka proteina prekursora amiloida β na funkciju retromera u modelima Alzheimerove bolesti." Doctoral thesis, University of Zagreb, School of Medicine, 2020. https://urn.nsk.hr/urn:nbn:hr:105:191606

Dominko, K. (2020). 'Utjecaj unutarstaničnoga kolesterola i C-terminalnoga odsječka proteina prekursora amiloida β na funkciju retromera u modelima Alzheimerove bolesti', Doctoral thesis, University of Zagreb, School of Medicine, accessed 22 November 2024, https://urn.nsk.hr/urn:nbn:hr:105:191606

Dominko K. Utjecaj unutarstaničnoga kolesterola i C-terminalnoga odsječka proteina prekursora amiloida β na funkciju retromera u modelima Alzheimerove bolesti [Doctoral thesis]. Zagreb: University of Zagreb, School of Medicine; 2020 [cited 2024 November 22] Available at: https://urn.nsk.hr/urn:nbn:hr:105:191606

K. Dominko, "Utjecaj unutarstaničnoga kolesterola i C-terminalnoga odsječka proteina prekursora amiloida β na funkciju retromera u modelima Alzheimerove bolesti", Doctoral thesis, University of Zagreb, School of Medicine, Zagreb, 2020. Available at: https://urn.nsk.hr/urn:nbn:hr:105:191606

Metadata
TitleUtjecaj unutarstaničnoga kolesterola i C-terminalnoga odsječka proteina prekursora amiloida β na funkciju retromera u modelima Alzheimerove bolesti
Title (english)The effect of intracellular cholesterol and C-terminal fragment of amyloid β precursor protein on retromer function in Alzheimer’s disease models
AuthorKristina Dominko
MentorNataša Jovanov Milošević (mentor)
MentorSilva Katušić Hećimović (komentor)
Committee memberGoran Šimić (predsjednik povjerenstva)
Committee memberMelita Šalković-Petrišić (član povjerenstva)
Committee memberSvjetlana Kalanj-Bognar (član povjerenstva)
Committee memberIvica Kostović (član povjerenstva)
GranterUniversity of Zagreb
School of Medicine
(Croatian Institiute for Brain Research)
Zagreb
Defense date and country2020-01-24, Croatia
Scientific / art field,
discipline and subdiscipline		BIOMEDICINE AND HEALTHCARE
Basic Medical Sciences
Neuroscience
Universal decimal classification
(UDC)		616 - Pathology. Clinical medicine
Abstract
Bolest Niemann-Pick tipa C (NPC), rijetka nasljedna bolest u kojoj se nakuplja kolesterol u kasnim endosomima i lizosomima, dijeli mnoga patološka obilježja s Alzheimerovom bolesti. Hipoteza ovog rada je da unutarstanično nakupljanje kolesterola ili C-termaninalnog odsječka proteina prekursora amiloida β (CTFβ/C99) u bolesti NPC dovodi do poremećaja funkcije retromera, ključnog proteinskog kompleksa endosomalno-lizosomalnog puta uključenog u prijenos proteina APP i BACE1. Ispitana je funkcija retromera in vitro i ex vivo u različitim regijama mozga mišjeg modela bolesti NPC. Istražen je i utjecaj nakupljanja ili smanjenja unutarstaničnog kolesterola i CTFβ/C99 na funkciju retromera. U ovom doktorskom radu pokazano je nakupljanje proteina retromera u povećanim endosomima stanica kojima nedostaje protein NPC1 (stanice CHO NPC1-null i neuroni NPC1 knockout miševa) te da je funkcija retromera ovisna o razini kolesterola. U mozgu NPC1 knockout miševa razina i smještaj retromera i retromernog receptora sorLA promijenjeni su već u najranijim stadijima bolesti. Disfunkcija retromera uključena je u promijenjeni aksonalni transport u neuronima NPC1 knockout miševa. Nakupljanje CTF-APP-a uzrokuje nakupljanje retromera unutar endosomalno-lizosomalng puta te mijenja ekspresiju gena uključenih u metabolizam kolesterola. Rezultati ove doktorske disertacije potvrđuju da je disfunkcija retromera uključena u neurodegenerativne procese u bolesti NPC. Stoga bi popravljanje funkcije retromera potencijalno moglo biti dio novog pristupa liječenja ovog neizlječivog neurodegenerativnog poremećaja.
Abstract (english)
Niemann-Pick type C (NPC), a rare inherited disease in which cholesterol accumulates in late endosomes and lysosomes, shares several pathological features with Alzheimer’s disease. We tested the hypothesis that intracellular accumulation of cholesterol or CTFβ/C99 in NPC disease causes dysfunction of retromer, the key protein complex within the endosomal-lysosomal pathway involved in the transport of APP and BACE1. The function of retromer was analysed in vitro and ex vivo. The role of cholesterol or CTFβ/C99 accumulation and depletion on retromer function was also tested. This doctoral dissertation shows retromer accumulation in enlarged endosomes in cells that lack NPC1 protein (CHO NPC1-null cells and neurons from NPC1 knockout mice) and that retromer function is dependent on cholesterol levels. In the brains of NPC1 knockout mice, levels and distribution of retromer proteins and retromer receptor sorLA were altered even in the earliest stages of the disease. Retromer dysfunction is involved in altered axonal transport in neurons from NPC1 knockout mice. The accumulation of CTFs causes accumulation of retromer in the endosomal-lysosomal pathway and affects the expression of genes involved in cholesterol metabolism. These results show that retromer dysfunction is involved in neurodegenerative processes in NPC disease. Thus, retrieval of retromer function may potentially represent a novel therapeutic approach against this untreateble neurodegenerative disorder.
Keywords
Keywords (english)
Languagecroatian
URN:NBNurn:nbn:hr:105:191606
Promotion2021
Study programmeTitle: Neuroscience
Study programme type: university
Study level: postgraduate
Academic / professional title: doktor/doktorica znanosti, područje biomedicine i zdravstvo (doktor/doktorica znanosti, područje biomedicine i zdravstvo)
Catalog URLhttps://katalog.nsk.hr/F/19IT7Y755V1NXQJPHCLYSQGPF6BLAPPF179HQ7FAXXMYBYGMV5-21203?func=find-e&request=Utjecaj+unutarstani%C4%8Dnoga+kolesterola+i+C-terminalnoga+odsje%C4%8Dka+proteina+prekursora+amiloida+%CE%B2+na+funkciju+retromera+u+modelima+Alzheimerove+bolesti&find_scan_code=FIND_NAS&adjacent=N&local_base=MF_WEB&x=49&y=20&filter_code_1=WLN&filter_request_1=&filter_code_2=WYR&filter_request_2=&filter_code_3=WYR&filter_request_3=&filter_code_4=WFM&filter_request_4=
Type of resourceText
Extent201 str.
File originBorn digital
Access conditionsOpen access
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Created on2021-03-04 10:35:36