Title Protein interaction partners of TRIOBP-1, and its effect on their aggregation in schizophrenia Title (croatian) Proteini interakcijski partneri TRIOBP-1 i njegov učinak na njihovu agregaciju u shizofreniji Author Maja Juković Mentor Nicholas James Bradshaw (mentor) Committee member Željka Maglica (predsjednik povjerenstva) Committee member Jelena Ban (član povjerenstva) Committee member Nicholas James Bradshaw (član povjerenstva) Granter University of Rijeka Defense date and country 2021-09-08, Croatia Scientific / art field, INTERDISCIPLINARY AREAS OF KNOWLEDGE Abstract Chronic mental illnesses are a group of conditions that include major depressive disorder, bipolar disorder and schizophrenia. These illnesses present with persistent psychiatric symptoms and affect 10.7% of the global population. The emphasis of this thesis is on schizophrenia and disrupted proteostasis as its possible source. This idea stemmed from recent studies that proposed that insoluble, misfolded proteins deposits may not be limited to neurodegenerative disorders, but exist in chronic mental illnesses as well. Several proteins are being investigated for their propensity to aggregate, however, it remains unclear whether these proteins aggregate alone, co-aggregate with each other or recruit other proteins as a part of the pathological processes.
In this thesis we studied the propensity of TRIOBP-1 to aggregate alone and its ability to recruit other proteins to co-aggregate by overexpressing these proteins in neuroblastoma cells. In the first part of research we tested TRIOBP-1 with six of its potential interaction partners, out of which only NDE1 was seen to co-aggregate. Hence, we propose the aggregation mechanism implicating TRIOBP-1 misassembly as responsible for recruiting NDE1 to co-aggregate as well. The second portion of the study focused on researching TRIOBP-1 co-aggregation partners among the proteins previously implicated in chronic mental illness. In these experiments, only DISC1 co-aggregated with TRIOBP-1. Experiments with non-aggregating TRIOBP-1 mutant suggest these proteins are interaction partners as well as co-aggregation partners.
Two out of ten tested proteins were seen to co-aggregate with TRIOBP-1, however, other proteins are not yet to be excluded from their possible involvement in schizophrenia. These newly discovered insoluble deposits could act as a potential biological markers and used for early schizophrenia diagnosis if discovered not to be limited to the brain. They may also provide a valuable insight in underlaying mechanism of non-genetic schizophrenia onset.
Abstract (croatian) Kronične mentalne bolesti su skupina poremećaja koji uključuju depresivni poremećaj, bipolarni poremećaj te shizofreniju. Ove bolesti karakteriziraju dugotrajni i razorni psihijatrijski poremećaji te zahvaćaju 10,7% svjetske populacije. Naglasak ovog rada je na shizofreniji i narušenoj proteostazi kao mogućeg izvora bolesti. Ova ideja je proizašla iz nedavnih istraživanja koja predlažu da nakupine netopljivih proteina nisu svojstvene samo neurodegenerativnim poremećajima, već se javljaju i kod kroničnih mentalnih bolesti. Trenutno se ispituje nekoliko proteina koji su pokazali sklonost agregaciji, no zasada ostaje nejasno agregiraju li sami, ko-agregiraju li međusobno ili pak uključuju dodatne proteine u patofiziološke procese.
U ovom radu ispitali smo sposobnost TRIOBP-1 da agregira samostalno i uključuje druge proteine u ko-agregaciju prekomjernom ekspresijom ovih proteina u stanicama neuroblastoma. U prvom dijelu istraživanja testirali smo TRIOBP-1 sa šest njegovih potencijalnih interakcijskih partnera, od kojih je pokazano da jedino NDE1 ko-agregira. Na temelju ovih rezultata predlažemo da je agregacijski mehanizam TRIOBP-1, koji uzrokuje njegovo pogrešno smatanje, odgovoran i za ko-aggregaciju NDE1. Drugi dio istraživanja odnosio se na ispitivanje ko-agregacijskih partnera TRIOBP-1 među proteinima za koje je poznato da su uključeni u kronične mentalne bolesti. U ovom dijelu pokazano je kako samo DISC1 ima sposobnost ko-agregacije s TRIOBP-1. Daljnji eksperimenti s ne-agregirajućim mutantom TRIOBP-1 upućuju na to da su DISC1 i TRIOBP-1 osim ko-aggregacijski partneri, također i interakcijski partneri.
Dva od ukupno deset testiranih proteina ko-agregirali su s TRIOBP-1, ipak, još uvijek se ne može u potpunosti isključiti njihova potencijalna uloga u shizofreniji. Ove neotopive nakupine proteina mogle bi se pokazati kao potencijalni biološki markeri i koristiti za rano otkrivanje shizofrenije ukoliko se pokaže da njihova prisutnost nije ograničena samo na mozak. Ova otkrića mogu pružiti vrijedni novi uvid u temeljne mehanizme nastanka shizofrenije koji nemaju genetski uzrok.
Keywords
Chronic mental illness
protein aggregation
TRIO-Binding Protein splice variant 1 (TRIOBP-1)
Disrupted in Schizophrenia 1 (DISC1)
Nuclear Distribution element 1 (NDE1)
Keywords (croatian)
Kronične mentalne bolesti
agregacija proteina
TRIO-Binding Protein splice variant 1 (TRIOBP-1)
Disrupted in Schizophrenia 1 (DISC1)
Nuclear Distribution Element 1 (NDE1)
Language english URN:NBN urn:nbn:hr:193:354007 Project Number: IP-2018-01-9424 Study programme Title: Drug research and development Type of resource Text File origin Born digital Access conditions Access restricted to students and staff of home institution Terms of use Created on 2021-09-07 17:42:15
