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Browsing by Subject "oxidative stress"

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  • Impact of cellular stressors on the localization and expression dynamics of mesencephalic astrocyte-derived neurotrophic factor 
    Ali Tsaous, Achmet (2024)
    Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) is an evolutionary conserved protein vital for regulating various physiological processes, with potential therapeutic applications for many conditions. MANF is primarily localized within the ER lumen; however, its intracellular localization and cellular trafficking during pathological conditions remain unclear. It has been shown that MANF is upregulated by ER stress and plays a crucial role in mitigating the unfolded protein response (UPR) by interacting with ER transmembrane sensors and chaperone proteins; additionally, MANF has demonstrated attenuating effects on oxidative stress and improved mitochondrial function. Therefore, this thesis aims to uncover the cellular intricacies of MANF, examining its potential nuclear translocation and expression dynamics under ER and oxidative stress conditions. Here, we show that MANF can localize into the cell nucleus, and various stress conditions alter the expression dynamics and localization of MANF. We detected MANF and some other ER-resident proteins in the nuclear fractions of cells and rat liver tissue in steady-state conditions in vitro. We found that MANF may translocate into the nucleus under stress-induced conditions. Furthermore, we showed expression dynamics of MANF and some other ER-resident proteins upon ER and oxidative stress in vitro. Our results demonstrate the dynamic localization and expression of MANF in response to ER and oxidative stress, revealing its potential involvement in cellular responses under stress conditions. These findings not only pave the way for further research into the precise roles and mechanisms of MANF but also inspire new areas for investigation, offering potential therapeutic implications for conditions that urgently require novel innovative treatments for patients.
  • Solustressi Parkinsonin taudin eläinmalleissa 
    Siekkinen, Jenni (2015)
    Parkinson's disease is a progressive neurodegenerative movement disorder which is characterized by the death of dopaminergic neurons in the substantia nigra. In addition, other neuropathological features of the disease are intracytoplasmic protein inclusions as well as oxidative and ER stress. Currently there is no cure for Parkinson's disease so there is a need for novel therapies which could stop the disease progression. Because neurotrophic factors can promote the survival of neurons they might be beneficial for the treatment of Parkinson's disease. Cerebral dopamine neurotrophic factor (CDNF) has proven to be neuroprotective and neurorestorative in rodent models of Parkinson's disease. However, the development of new therapies requires relevant disease models. The defects of the current models of Parkinson's disease increases the need for better and more descriptive disease models. The literature review of this thesis presents an overview of ER stress and oxidative stress. Their role in Parkinson's disease 6-OHDA, MPTP, α-synuclein and rotenone models is also reviewed. The experimental part consists of three studies. The aim of the first study was to establish a preformed α-synuclein fibril mouse model of Parkinson's disease. The development of the lesion was studied by testing the motoric skills with balance beam, rotarod, wire hanger and cylinder test. In addition, TH and α-synuclein immunostainings from striatum and substantia nigra sections was performed. In the second study the effect of CDNF on mice behaviour and TH- and α-synuclein-immunoreactivity in the α-synuclein fibril mouse model was examined. The same motoric behaviour tests as in the first study were used. The purpose of the third experimental part was to investigate the effect of CDNF and GDNF on ER stress proteins in 6-OHDA rat model of Parkinson's disease. The levels of ER stress markers GRP78 and phosphorylated eIF2α were analyzed by Western Blot. The results of the studies were promising. In further studies the effect of α-synuclein fibrils on mouse behaviour and TH- and α-synuclein-immunoreactivity could be studied for longer time. The effect of CDNF on α-synuclein aggregation could also be studied further. The expression levels of other ER stress markers could be investigated so it would clarify the effect of CDNF and GDNF on ER stress.

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