The Intersection of Neurodegeneration and Mitochondrial Stress in Caenorhabditis Elegans Models of Parkinson's Disease

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons, particularly in the substantia nigra region of the brain. One of the key pathological hallmarks of PD is the accumulation of the misfolded protein, α-synuclein (α-syn). Emerging evidence suggests an interplay between α-syn and mitochondria leads to a disruption of mitochondrial function, impaired energy production, and increased oxidative stress. During stress, the transcription factor, ATFS-1, orchestrates the mitochondrial unfolded protein response (UPRmt). Stressors, such as protein misfolding, trigger ATFS-1 to localize to the nucleus, where it activates the expression of over 400 molecular chaperones, proteases, and other proteins. Using Caenorhabditis elegans PD model in which human α-syn is overexpressed, we found that the atfs-1 loss-of-function mutation constitutively inactivates the UPRmt, resulting in decreased neurodegeneration. We hypothesized that this attenuation of neurodegeneration observed in the absence of afts-1 activity reflects diminished levels of UPRmt gene products that accumulate in the cytosol due to a constitutive blockade of mitochondrial import caused by chronic α-syn accumulation. Therefore, we performed a forward genetic screen to identify potential genes that modulate α-syn-induced dopaminergic neurodegeneration. We found two histone demethylases, jmjd-1.2 and jmjd-3.1, both known to be required for UPRmt activation, and twk-14, a gene encoding a potassium channel protein, with no prior association to PD or UPRmt. This study shapes our understanding of the relationship between α-syn and mitochondria in the context of PD and highlights potential therapeutic targets aimed at mitigating disease progression. Few PD cases are attributed to a specific genetic mutation, thus environmental toxins must be investigated. When individuals with a genetic predisposition to PD are also exposed to environmental toxins, their risk is increased. We found that common soil bacteria, Streptomyces venezuelae (S. ven) produce metabolites that cause neurodegeneration in C. elegans and human cell cultures. Transgenic worms chronically expressing α-syn in dopamine neurons display enhanced neurodegeneration when treated with S. ven metabolite. We performed a transcriptomic analysis to investigate the gene expression patterns augmented by S. ven metabolite exposures. This study provides insight into the complexities of organismal response to neurotoxic exposures in a gene-by-environment model of PD.

Grantor dc:publisher

University of Alabama Libraries

Year dc:date.issued

2024

Author dc:creator

• Willicott, Karolina

Advisor dc:contributor.advisor

• Caldwell, Kim A.

Contributors dc:contributor

• Caldwell, Guy A.
• Chtarbanova-Rudloff, Stanislava
• Ciesla, Lukasz
• Fierst, Janna

• ATFS-1
• jmjd-3.1 jmjd-1.2
• Streptomyces venezuelae
• synuclein
• twk-14
• UPRmt

Statement dc:rights

• All rights reserved by the author unless otherwise indicated.

Language dc:language.iso

en_US, English

Dc Identifier Other

1089199

OAI identifier oai:identifier

oai:ir.ua.edu:123456789/14450