Cue the stress: Malaria parasites employ canonical and novel stress granules as a developmental mechanism
Open Access
- Author:
- Munoz, Elyse Elaine
- Graduate Program:
- Genetics
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 16, 2017
- Committee Members:
- Robert Paulson, Dissertation Advisor/Co-Advisor
Manuel Llinas, Committee Chair/Co-Chair
Andrew David Patterson, Committee Member
David Scott Gilmour, Committee Member
David Scott Gilmour, Outside Member
Robert Paulson, Program Head/Chair - Keywords:
- Malaria
Plasmodium yoelii
Plasmodium
stress response
ALBA4 - Abstract:
- Organisms employ multiple molecular mechanisms to respond to environmental stresses to increase their chances of survival. One of the most well-known mechanisms, the formation of stress granules, has been well-characterized in yeast. These stress granules form in response to many different stimuli, including glucose deprivation, amino acid starvation, heat shock, and oxidative stress. Recently, stress granules have been indicated in human neurodegenerative diseases, including Alzheimer’s disease and dementia. As the ability to clear stress granules decreases, proteins with “sticky regions” are left in the cytoplasm, and begin to coacervate, leading to cell-wide dysfunction that, if left unresolved, results in cell death. This is akin to what is seen in prion diseases, wherein the misfolding of certain proteins allows their aggregation, also resulting in cell death. The formation of stress-granule like complexes have been identified in Plasmodium, the causative agent of malaria. This allows the parasite to generate mRNA transcripts when resources are plentiful and retain them throughout the arduous task of transmission. Then, as the parasite reaches its intended location, the parasite can then release these protected transcripts to allow for their translation and action of the encoded proteins. To this end, characterization of a RNA-binding protein known to be a member of stress-granule like complexes found in Plasmodium species was performed. This protein, ALBA4, has an ancient protein lineage, yet is apicomplexan-specific. The absence of this protein was found to have interesting phenotypes in the transmitted forms of the parasites, including dysregulation of transcripts consistent with the phenotypes. As this RNA homeostasis is critical for the parasite life cycle, this protein is an attractive target to interrogate the underlying basic biology of these stress granules in the parasite context. By performing immunoprecipitations of ALBA4, it was revealed it associates not only with canonical stress granules, but also with mRNA degradative machinery and active translation machinery, highlighting the complexity and dynamic nature of these membrane-less organelles. Finally, experimentation reveals ALBA4 functions are life cycle stage-dependent, again underscoring the complexity of the basic biology employed by this parasite. Taking these observations together, stress granules are a viable target for therapeutic intervention. The native proteins found within Plasmodium stress granules that contain intrinsically disordered regions, including ALBA4, and a deeper understanding of the clearance of these stress granules, will lead to deeper parallels between yeast and neurodegenerative and prion diseases. By drawing these parallels, it is possible to generate a Plasmodium control strategy centered on perturbing stress granules and/or introducing misfolded peptides that mimic prion proteins. By focusing on the transmission events, this strategy can have the greatest effect at curtailing the spread of this deadly parasite.