Utjecaj unutarstaničnoga kolesterola i C-terminalnoga odsječka proteina prekursora amiloida β na funkciju retromera u modelima Alzheimerove bolesti

doctoral thesis

• Title (english): The effect of intracellular cholesterol and C-terminal fragment of amyloid β precursor protein on retromer function in Alzheimer’s disease models
• Author: Kristina Dominko
• Mentor: Nataša Jovanov Milošević (mentor)
• Mentor: Silva Katušić Hećimović (komentor)
• Committee member: Goran Šimić (predsjednik povjerenstva)
• Committee member: Melita Šalković-Petrišić (član povjerenstva)
• Committee member: Svjetlana Kalanj-Bognar (član povjerenstva)
• Committee member: Ivica Kostović (član povjerenstva)
• Granter: University of Zagreb; School of Medicine; (Croatian Institiute for Brain Research); Zagreb
• Defense date and country: 2020-01-24, 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: Alzheimerova bolest; funkcija retromera; Niemann-Pick tipa C
• Keywords (english): Alzheimer’s disease; retromer function; Niemann-Pick type C
• Language: croatian
• URN:NBN: urn:nbn:hr:105:191606
• Promotion: 2021
• Study programme: Title: 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 URL: https://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 resource: Text
• Extent: 201 str.
• File origin: Born digital
• Access conditions: Open access
• Created on: 2021-03-04 10:35:36