Therapeutic strategies of Parkinson's disease: Alternative dopamine replacement and potential drug targets

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2022-08
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Abdalla , Ahmed Abdulrahman
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Kanthasamy, Anumantha G
Martin, Richard J
Kanthasamy, Arthi
Mochel, Jonathan Paul M.
Gupta, Mohan
Bai, Hua
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Veterinary Biomedical Sciences
Abstract
The complex and prolonged disease course exhibited by Parkinson's disease (PD) first starts with non-motor disturbances and then slowly progresses to mild-to-moderate motor deficits, ultimately inflicting severe movement impairment and cognitive decline. Dopamine deficiency resulting from dopaminergic neuronal degeneration in substantia nigra (SN), known to be linked to mitochondrial dysfunction, ultimately manifests as the cardinal extrapyramidal motor symptoms of rigidity, bradykinesia, tremors, and postural instability. These symptoms are due to loss of dopamine (DA) from dopaminergic neurons in the SN region, but the etiology and the pathophysiology behind it are still not fully understood. Currently, no treatment capable of stopping this neurodegeneration, and DA replacement via oral tablet dosing of L-DOPA/carbidopa or benserazide 3-4 times/day remains the most effective and well-tolerated treatment, one that significantly improves the motor symptoms and quality of life of patients in the early stages of PD. However, due to L-DOPA's non-continuous, pulsatile delivery to the brain, long-term L-DOPA administration causes deleterious side effects, including L-DOPA-induced dyskinesia (LID), among other motor complications, in most patients. Thus, emerged the urgent need to overcome L-DOPA's toxic side effects and increase its efficacy to improve quality of life. Moreover, the need for identifying a new therapeutic target that can prevent continuous neurodegeneration is highly required. Chapter 2 of this dissertation provides evidence that a novel approach of using systemic delivery of genetically engineered, plasmid-based, and regulatable L-DOPA-producing probiotic bacteria will avoid fluctuations in plasma L-DOPA levels and provide more consistent delivery of L-DOPA to the brain where L-DOPA can be converted to a continuous supply of dopamine in the nigrostriatal pathway. Our results indicated that generated EcNLDOPA probiotic strains could produce a significant amount of L-DOPA both in vitro and in vivo to achieve stable plasma L-DOPA levels resulting in sustained symptomatic relief without severe L-DOPA-associated motor complications, including dyskinesia. Additionally, our data suggest that using microbiome therapy can provide extra benefit to patients as the improved L-DOPA delivery to the brain was associated with a significant improvement in non-motor symptoms of PD. In chapter 3, we are trying to understand a novel role of major histone acetyltransferase enzyme Elongator complex protein subunit 3 (ELP3), believed to play a significant role in neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Exploring the role of ELP3 after mitochondrial stress in response to toxic insults will strengthen understanding of novel factors controlling epigenetic response and mitochondrial health contributing to neurodegeneration. Our data suggest that ELP3 expression increases post mitochondrial stress and similar increases in SN brain regions of PD patients. This increase in ELP3 expression was associated with changes in ELP3 mitochondrial localization, specific histone acetylation, and methylation sites. This work opens the door for investigating an important factor controlling the epigenetic response and mitochondrial dysfunction in PD.
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