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Mechanisms of Neurodegeneration and Neuroprotection in Parkinson’s and Alzheimer's Disease

Ismael, Sazan Khalid
http://orcid.org/0000-0001-5160-0653
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1565615884263425

Abstract Details

2019, Doctor of Philosophy (PhD), Ohio University, Biological Sciences (Arts and Sciences).
The purpose of this research is to study molecular mechanisms underlying neurodegeneration and possible neuroprotective strategies for both Parkinson’s disease (PD) and Alzheimer’s disease (AD). PD is a progressive movement disorder characterized by selective loss of dopaminergic (DA) neurons in substantia nigra pars compacta and Lewy Bodies, cytoplasmic deposits of proteins including αSyn (Islam et al., 2012). Currently levodopa, dopamine precursor, and D2 receptor agonists are the most effective therapeutic drugs for controlling PD symptoms and providing patients a better life, but none of them yet prevent PD progression (Ceravolo et al., 2016; Kitamura et al., 2003) . Therefore, demand on neuroprotective strategies is still very high (Lohle & Reichmann, 2010). In my project, by using larval locomotion assays and primary neuronal culture of Drosophila melanogaster, I model PD with an environmental PD toxin rotenone to investigate molecular mechanisms of neuroprotection. Larval locomotion parameters, locomotion speed, angular velocity and pause time, are used in order to support the similarity in motor defects between larval Drosophila major model and human PD. I show that modulating cAMP signaling pathway in DA neurons can protect against rotenone-induced DA neurodegeneration, and this neuroprotection is mediated by PKA activation. I also show that αSyn (A53T), a mutant form of αSyn that is linked to PD, aggregates are increased with rotenone application, and these aggregates have capability to propagate in our culture system. Furthermore, I show αSyn secretion is modulated by neuronal stimulation. Due to considerable overlap between pathology of αSyn and tau aggregates, a hallmark of AD (Roy & Jackson, 2014), I expanded my research work to further explore tau pathology using flies that express human tau (hTau). This hTau was toxic when expressed in cholinergic neurons in the culture system with increasing the number of aggregates in their neurites over time. These hTau aggregates were transferred to other neurons that are not expressing hTau. Moreover, I found that hTau can be secreted to the media as an active process, which was regulated, by neuronal activity and their phosphorylation state. This secreted hTau in the extracellular space is highly phosphorylated at multiple sites in proline-rich domain. I conclude that activation of PKA signaling pathway is neuroprotective in rotenone-induced PD-like model, and αSyn and hTau secretion is enhanced by neuronal stimulations in fly primary neuronal culture. These results provide novel findings that expand our knowledge about mechanisms underlying PD and AD pathology, which might be potential avenues for developing therapeutic treatments against PD and AD progression.
Daewoo Lee (Advisor)
Biology; Cellular Biology; Molecular Biology; Nanoscience
Parkinsons Disease; Alzheimers Disease; Tau alpha synuclein

Recommended Citations

Citations

  • Ismael, S. K. (2019). Mechanisms of Neurodegeneration and Neuroprotection in Parkinson’s and Alzheimer's Disease [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1565615884263425

    APA Style (7th edition)

  • Ismael, Sazan. Mechanisms of Neurodegeneration and Neuroprotection in Parkinson’s and Alzheimer's Disease. 2019. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1565615884263425.

    MLA Style (8th edition)

  • Ismael, Sazan. " Mechanisms of Neurodegeneration and Neuroprotection in Parkinson’s and Alzheimer's Disease." Doctoral dissertation, Ohio University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1565615884263425

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Ohio University and OhioLINK.