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Babinchak WM Dissertation.pdf (16.57 MB)

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Pathological Aggregation and Liquid-Liquid Phase Separation of TDP-43 in Neurodegenerative Disease

Babinchak, William Michael
http://orcid.org/0000-0002-8299-287X
http://rave.ohiolink.edu/etdc/view?acc_num=case158575494511376

Abstract Details

2020, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Protein aggregation is a pathological hallmark of many neurodegenerative diseases. In these diseases, proteins misfold and assemble into ordered filaments, known as amyloid fibrils. These aggregates have a unique structure that is believed to underlie their toxicity to the brain. Therefore, immense effort has been put toward understanding their architectures and mechanisms of assembly. More recently, liquid-liquid phase separation (LLPS) of proteins was revealed to underlie the formation of membrane-less organelles within the cell. However, the intrinsically disordered proteins that undergo phase separation also have a great propensity to form amyloid aggregates. Accordingly, LLPS has been proposed to mediate the formation of amyloid fibrils and, consequently, the prevention of aberrant phase transitions deemed of therapeutic value. This work describes three interrelated areas of research. In the first, the relationship between LLPS and amyloid aggregation for a specific protein, TDP-43, is described: LLPS per se can promote amyloid aggregation. In the second, the structures of these amyloid aggregates formed by TDP-43 are investigated in addition to the role that LLPS has in structural permutations. Finally, the capacity for a small molecule to greatly modulate the LLPS of TDP-43, among many other important proteins, is demonstrated. The mechanism by which this regulation occurs and the chemical features that impart this capacity are also described. In all, each of these studies emphasizes the intersection between LLPS and protein aggregation, providing insights into the molecular basis of protein aggregation in disease and potential therapeutic avenues.
Sudha Chakrapani (Committee Chair)
Eckhard Jankowsky (Committee Member)
Alberto Costa (Committee Member)
Matthias Buck (Committee Member)
Blanton Tolbert (Committee Member)
Witold Surewicz (Advisor)
204 p.
Biochemistry; Biophysics; Condensation
Liquid-liquid phase separation, TDP-43, neurodegeneration, amyloid, aggregation

Recommended Citations

Citations

  • Babinchak, W. M. (2020). Pathological Aggregation and Liquid-Liquid Phase Separation of TDP-43 in Neurodegenerative Disease [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case158575494511376

    APA Style (7th edition)

  • Babinchak, William. Pathological Aggregation and Liquid-Liquid Phase Separation of TDP-43 in Neurodegenerative Disease. 2020. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case158575494511376.

    MLA Style (8th edition)

  • Babinchak, William. "Pathological Aggregation and Liquid-Liquid Phase Separation of TDP-43 in Neurodegenerative Disease." Doctoral dissertation, Case Western Reserve University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case158575494511376

    Chicago Manual of Style (17th edition)

case158575494511376
108
© 2020, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.