| Abstract | Mental health is an essential part to of our overall well-being and
human rights, ranging from complete wellbeing to severe emotional
distress. Several risk factors contribute to these diseases, including
psychological and biological components such as genetics and
emotional abilities, which can often be altered by changes in brain
structure and function. Common mental health disorders, including
schizophrenia, bipolar disorder, and major depressive disorder, cause
significant disturbances in behaviour, cognition, and emotional
control, resulting in distress and functional impairment.
Proteins are essential for cellular functions and must fold correctly so
they can perform their functions. However, proteins can misfold and
aggregate, especially under certain conditions, resulting in toxic
aggregates. Normally, cellular quality control systems, such as the
ubiquitin-proteasome system and autophagy, manage these
aggregates. When these mechanisms fail, protein misfolding
diseases, often known as proteinopathies, develop, including
neurodegenerative disorders such as Alzheimer's, Parkinson's, and
Huntington's. These disorders are characterized by toxic protein
aggregation which leads to neuronal dysfunction and cell death,
linking proteinopathies to cognitive decline and psychiatric
symptoms.
The correlation between mental illness and proteinopathies is
becoming increasingly recognised. Proteins such as DISC1 and
TRIOBP-1 have been observed to aggregate in mental illnesses,
suggesting that they play important roles in the pathophysiology of
these conditions.
This thesis focused on providing an insight into the behaviour of
TRIOBP-1 and DISC1 in neuronal cells, allowing us to investigate the
behaviour of these proteins and their potential connection to mental
diseases. The primary aim was to determine the most optimal dose
of doxycycline and period of treatment for protein expression,
followed by the detection of protein aggregation by Western blotting,
fluorescent microscopy, and insolubility assays. By demonstrating
these proteins' aggregation tendencies, trying to contribute to the
understanding of how protein misfolding may connect to
neurodevelopmental diseases |
| Abstract (croatian) | Mentalno zdravlje je ključni dio općeg blagostanja i ljudskih prava,
kreće se od potpunog blagostanja do teške emocionalne patnje.
Nekoliko čimbenika rizika doprinosi ovim bolestima, uključujući
psihološke i biološke komponente poput genetike i emocionalnih
sposobnosti, koje se često mogu promijeniti zbog promjena u
strukturi i funkciji mozga. Uobičajeni poremećaji mentalnog zdravlja,
uključujući shizofreniju, bipolarni poremećaj i veliki depresivni
poremećaj, uzrokuju značajne poremećaje u ponašanju, kogniciji i
emocionalnoj kontroli, što rezultira stresom i funkcionalnim
oštećenjima.
Proteini su ključni za stanične funkcije i moraju se pravilno saviti kako
bi mogli obavljati svoje funkcije. Međutim, proteini se mogu
nepravilno saviti i agregirati, osobito u određenim uvjetima, što
rezultira stvaranjem toksičnih agregata. Normalno, stanični sustavi
kontrole kvalitete, poput sustava ubikvitin-proteasoma i autofagije,
upravljaju ovim agregatima. Kada ti mehanizmi zakažu, razvijaju se
bolesti uzrokovane nepravilnim savijanjem proteina, poznate kao
proteinopatije, uključujući neurodegenerativne poremećaje poput
Alzheimerove, Parkinsonove i Huntingtonove bolesti. Ovi poremećaji
karakterizirani su toksičnim agregacijama proteina koje dovode do
disfunkcije neurona i stanične smrti, povezujući proteinopatije s
kognitivnim padom i psihijatrijskim simptomima.
Povezanost između mentalnih bolesti i proteinopatija sve se više
prepoznaje. Primijećeno je da proteini poput DISC1 i TRIOBP-1
agregiraju u mentalnim bolestima, što sugerira da oni imaju važnu
ulogu u patofiziologiji ovih stanja.
Ovaj se rad usredotočio na pružanje uvida u ponašanje TRIOBP-1 i
DISC1 u neuronskim stanicama, što nam omogućuje da istražimo
ponašanje tih proteina i njihovu potencijalnu povezanost s mentalnim
bolestima. Primarni cilj bio je utvrditi optimalnu dozu doksiciklina i
razdoblje tretmana za ekspresiju proteina, nakon čega slijedi
detekcija agregacije proteina pomoću Western blottinga,
fluorescentne mikroskopije i ispitivanja netopivosti. Dokazivanjem
sklonosti agregaciji ovih proteina, pokušava doprinijeti razumijevanju
kako nepravilno savijanje proteina može biti povezano s
neurodegenerativnim bolestima. |
