Otkrivanje ranih neuropatoloških promjena u miševa prenositelja bolesti Niemann-Pick tipa C

master's thesis

• Title (english): Detection of the early neuropathological changes in mice Niemann-Pick type C disease carriers
• Author: Lovro Martinović
• Mentor: Silva Katušić Hećimović (mentor)
• Mentor: Julija Erhardt (komentor)
• Committee member: Julija Erhardt (predsjednik povjerenstva)
• Committee member: Inga Urlić (član povjerenstva)
• Committee member: Petra Peharec Štefanić (član povjerenstva)
• Committee member: Maja Matulić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2023-02-21, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Bolest Niemann-Pick tipa C (NPC) je monogenska, autosomno recesivna, smrtonosna
neurodegenerativna bolest, uzrokovana mutacijama u genima NPC1 ili NPC2 koji kodiraju za
transportere kolesterola iz kasnih endosoma/lizosoma. Smatralo se da su prenositelji bolesti
NPC, koji imaju mutaciju u jednom alelu gena NPC1/2, potpuno zdravi, dok se nisu primijetile
određene neuropsihijatrijske promjene u starijoj dobi. Također, istraživanja na mišjem modelu
NPC1 heterozigota (NPC1-het) ukazuju na pojavu neurodegeneracije i neuroinflamacije u
starijoj dobi. Cilj diplomskog rada bio je utvrditi najranije neuropatološke promjene u
prenositelja bolesti NPC, tj. u kori velikog mozga, hipokampusu i malom mozgu 20 i 40 tjedana
starih miševa NPC1-het u odnosu na miševe divljeg tipa (WT) iste starosti. Rezultati
imunohistokemijske analize hipokampusa pokazuju pojavu aktivacije astrocita (biljeg GFAP)
u miševa NPC1-het starih 20 tjedana. Otkriveno je i povećano bojanje lizosoma (biljeg Lamp1)
te nakupljanje kolesterola (bojanje filipinom) u miševa NPC1-het starih 20 i 40 tjedana u svim
analiziranim moždanim regijama u odnosu na uzorke WT. Dobiveni rezultati ukazuju da bi
prenositelji bolesti NPC mogli pokazivati ključne neuropatološke karaktersitike bolesti NPC,
uključujući nakupljanje kolesterola, disfunkciju lizosoma i neuroinflamaciju. Daljnja
istraživanja su neophodna kako bi se dodatno razjasnile uočene promjene na mišjem kao i na
humanom modelu prenositelja bolesti NPC.

Abstract (english)

Niemann-Pick type C disease (NPC) is a monogenic, autosomal recessive, fatal
neurodegenerative disorder, caused by mutations in the NPC1 or NPC2 genes that code for
cholesterol transport proteins from late endosomes/lysosomes. Carriers of NPC disease, who
have a mutation in only one allele of the NPC1/2 genes, were considered healthy, until certain
neuropsychiatric changes were recently observed in their old age. Moreover, studies of the aged
brains of NPC1 heterozygous mice (NPC1-het) indicated neurodegeneration and
neuroinflammation. The aim of this thesis was to investigate the earliest neuropathological
changes in carriers of the NPC disease, i.e. in the cerebral cortices, hippocampi and cerebella
of 20 and 40-weeks-old NPC1-het mice compared to wild-type (WT) mice of the same age.
Immunohistochemical analysis of the hippocampi identified activation of astrocytes (marker
GFAP) in 20-weeks-old NPC1-het mice. Increased lysosomal staining (Lamp1 marker) and
cholesterol accumulation (filipin staining) were also detected in all analyzed brain regions of
20 and 40-weeks-old NPC1-het mice vs. WT samples. The obtained results indicate that carriers
of NPC disease may exert key neuropathological features of NPC disease, including cholesterol
accumulation, lysosomal dysfunction and neuroinflammation. Further studies are necessary to
elucidate the observed changes in the mouse model as well as the human model of the NPC
disease carriers.

• Keywords: kolesterol; NPC1; lizosom; neurodegeneracija; neuroinflamacija; rijetke bolesti
• Keywords (english): cholesterol; NPC1; lysosome; neurodegeneration; neuroinflammation; rare diseases
• Language: croatian
• URN:NBN: urn:nbn:hr:217:715744
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: graduate; Academic / professional title: magistar/magistra molekularne biologije (magistar/magistra molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Embargoed access; Embargo expiration date: 2025-02-21
• Created on: 2023-03-01 13:27:35