Uloga proteina toplinskog stresa u nastanku, razvoju i terapiji neurodegenerativnih bolesti

master's thesis

• Title (english): The role of heath shock proteins in onset, progression and therapy of neurodegenerative diseases
• Author: Iva Žurić
• Mentor: Karmela Barišić (mentor)
• Committee member: Karmela Barišić (predsjednik povjerenstva)
• Committee member: Donatella Verbanac (član povjerenstva)
• Committee member: Maja Ortner Hadžiabdić (član povjerenstva)
• Granter: University of Zagreb; Faculty of Pharmacy and Biochemistry; (Department of medical biochemistry and haematology); Zagreb
• Defense date and country: 2019-07-11, Croatia
• Scientific / art field, discipline and subdiscipline: BIOMEDICINE AND HEALTHCARE; Pharmacy; Pharmacy

Abstract

Sve stanice živoga organizma nastoje održati regularan promet proteina u stanici i njihovu ispravnu
komformaciju što se zajedničkim imenom naziva proteostaza. Neuroni su, zbog svoje post-mitotičke prirode i
intenzivnog metabolizma, posebno podložni poremećajima proteostaze koje uzrokuju stresni podražaji. Starenje,
zajedno sa nasljednim genetskim mutacijama, dovodi do disfunkcije tih sustava i razvoja neurodegenerativnih bolesti
(NDD-a).
NDD su jako česte u današnjoj populaciji zbog sve duljeg životnog vijeka stanovništva. One sa sobom nose
teške kognitivne i motoričke disfunkcije koje pacijentu značajno umanjuju kvalitetu života. Terapijska strategija koja
za sada najviše obećava je povećanje koncentracije molekulskih šaperona koje bi spriječilo nastanak toksičnih
proteinskih agregata i umanjilo štetan utjecaj onih koji su već nastali.
Prilikom izrade ovog diplomskog rada korišteni su znanstveni radovi dostupni u bazama podataka PubMed,
Nature i ScienceDirect, te knjiga Cooper GM i Hausman RE, Stanica: Molekularni pristup.
Svim NDD-ovima zajednička je pojava toksičnih proteinskih inkluzija koje su rezultat smanjene
funkcionalnosti sustava za održavanje proteostaze i zbog toga se skupno nazivaju proteinopatije. Neovisno o tome koji
mutirani protein je prisutan u neuronu, mehanizmi proteotoksičnosti vrlo su slični kod svih proteinopatija. U jezgri
dolazi do sekvestracije genetskih i epigenetskih faktora, u citoplazmi toksične inkluzije dovode do disfunkcije brojnih
sustava za održavanje proteostaze, dok u mitohondrijima dolazi do oksidativnih oštećenja. Proteini toplinskog stresa
(Hsp) čine iznimno bitnu komponentu svih sustava za održavanje proteostaze u stanici. Nedavna otkrića upućuju na
činjenicu da Hsp, osim te temeljne uloge, imaju još i cijeli niz drugih uloga od kojih su neke sudjelovanje u
apoptotičkim kaskadama, upali i imunosnim procesima u živčanom sustavu. Najnovije terapijske strategije obuhvaćaju
inhibiciju Hsp90, modulaciju upale u središnjem živčanom sustavu putem α-kristalina i membransku lipidnu terapiju.

Abstract (english)

All living cells are trying to maintain proper protein circulation inside the cell and to keep all proteins in their
correct conformation. These processes are collectively named proteostasis. Neurons are, due to their post-mitotic
nature and intense metabolism, extremely susceptible to proteostasis disturbances which are caused by stress stimulies.
Ageing, combined with hereditary genetic mutations, leads to system disfunctions which causes neurodegenerative
disease (NDD) development.
Nowdays, NDDs are extremely common due to prolonged life expectancy. They tend to cause cognitive and
motoric disfunctions that reduce patients life quality significantly. Therapeutic strategy that has shown the best results
till now is increasing molecular chaperones concentration which is supposed to stop mutant proteins aggregation and
reduce toxic potential of those that are already present.
This thesis is based on scientific articles that can be found in data bases PubMed, Nature and ScienceDirect.
The book Copper GM and Hausman RE, The Cell: a molecular approach, was also used as a source of information.
Toxic protein inclusions, which result from decreased protein quality control systems efficiacy, can be found in
all types of NDDs that are collectively named proteinopaties. Proteotoxic mechanisms are very similar in all NDDs
and they do not depend on mutant protein type. In cell nucleus, mutant proteins sequestrate genetic and epigenetic
factors. In cytoplasm, they lead to protein quality control system disfunctions whereas in mitochondria they cause
oxidative damage. The latest research show that Hsps, except their usual rolle in protein quality control, take part in
variety of other processes such as apoptotic cascades, inflamation and imunologic reactions in central nervous system.
Recently discovered therapeutic strategies include Hsp90 inhibition, modulation of α-cristallins and memnbrane lipid
therapy.

• Keywords: neurodegenerativne bolesti; proteinski agregati; molekulski šaperoni; proteotoksičnost
• Keywords (english): neurodegenerative disease; protein aggregates; molecular chaperones; proteotoxicity
• Language: croatian
• URN:NBN: urn:nbn:hr:163:851777
• Study programme: Title: Pharmacy; Study programme type: university; Study level: integrated undergraduate and graduate; Academic / professional title: magistar/magistra farmacije (magistar/magistra farmacije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2020-02-12 13:19:50