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Glebov-McCloud Alex - Thesis - 2026-04-287.25 MB
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Dissertation
Mechanisms driving neurological disorders caused by variants in PRKAR1B
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008390
Abstract
Neurological disorders (NLDs) are disorders that affect the nervous system and include both neurodegenerative (NDGDs) and neurodevelopmental disorders (NDDs). NLDs affect billions of people globally and exert a significant healthcare burden. This dissertation investigates the underlying mechanisms of two NLDs caused by variants in protein kinase A (PKA).
PKA is a key regulator of cell signaling and is essential for early life development, particularly because it is involved in numerous physiological processes, including glucose metabolism, cardiomyocyte contraction, as well as learning and memory. PKA exists as a heterotetrameric holoenzyme composed of two catalytic (C) and two regulatory (R) subunits. The holoenzyme is activated upon binding of 3',5'-cyclic adenosine monophosphate (cAMP) to the R subunits, leading to the initiation of downstream signaling events. PKA regulates several distinct physiological processes in part due to the existence of distinct, functionally non-redundant C and R subunit isoforms, which are expressed in a tissue-specific manner. Recent reports have identified NLD-causing variants in the brain-specific PKA regulatory RIβ subunit, encoded by the PRKAR1B gene.
In the first part of this dissertation, we investigate the L50R RIβ variant that causes the disorder termed neuronal loss and parkinsonism driven by a PKA mutation (NLPD-PKA). NLPD-PKA is characterized clinically by dementia and parkinsonism and pathologically by the formation of neuronal inclusions in brain tissue. Our work shows that RIβ normally undergoes liquid-liquid phase separation (LLPS) to form highly concentrated, dynamic pools of protein called biomolecular condensates as a means of spatially regulating PKA signaling. However, the L50R variant disrupts the spatial regulation of RIβ, resulting in the formation of static
condensates that impair PKA signaling. This work highlights the importance of the spatial regulation of PKA, disruptions in which can result in neurodegeneration.
In the second part of this dissertation, we investigate several RIβ variants (Q167L, E196K, R243C, and R335W) that cause the novel NDD Marbach-Schaaf neurodevelopmental syndrome (MASNS). MASNS is clinically characterized by global developmental delay, motor skill deficits, and high pain tolerance. Our work shows that these MASNS variants alter the catalytic activity and LLPS properties of PKA to varying degrees due to impaired cAMP sensitivity. This ultimately results in downstream signaling deficits, particularly with the R243C and R335W variants. These findings suggest that PKA is tightly regulated to ensure appropriate physiological signaling in the brain.
Together, our work reveals the complex mechanisms that regulate PKA signaling. Specifically, we show that PKA is critically modulated by both spatial regulation and cAMP sensitivity. Alterations in either of these properties by variants in the RIβ subunit contributes to both NLPD-PKA and MASNS. Our work thus elucidates the underlying mechanisms of these disorders, which may be potential targets for the development of therapeutics for affected patients.
Details
- Title: Subtitle
- Mechanisms driving neurological disorders caused by variants in PRKAR1B
- Creators
- Alexander G. P. Glebov-McCloud
- Contributors
- Stefan Strack (Advisor)Yuriy Usachev (Committee Member)Eric Taylor (Committee Member)Samuel Stephens (Committee Member)Snehajyoti Chatterjee (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Biomedical Science (Molecular Medicine)
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008390
- Publisher
- University of Iowa
- Number of pages
- xvii, 269 pages
- Copyright
- Copyright 2026 Alexander G. P. Glebov-McCloud
- Language
- English
- Date submitted
- 04/24/2026
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 241-269).
- Public Abstract (ETD)
Neurological disorders (NLDs) are disorders that affect the brain and include both neurodegenerative (NDGDs) and neurodevelopmental disorders (NDDs). NLDs affect billions of people globally and are a major healthcare concern.
Recent studies suggest that changes (variants) in the gene PRKAR1B cause NLDs. PRKAR1B encodes the brain-specific regulatory RIβ subunit of protein kinase A (PKA), a protein with important functions throughout the body. In the brain, PKA plays a role in learning and memory. The NLDs linked to RIβ variants include the new NDGD termed neuronal loss and parkinsonism driven by a PKA mutation (NLPD-PKA) and the new NDD termed Marbach-Schaaf neurodevelopmental syndrome (MASNS). Specifically, the RIβ variant L50R is linked to NLPD-PKA and the RIβ variants Q167L, E196K, R243C, and R335W are linked to MASNS.
Patients with NLPD-PKA show signs of parkinsonism and dementia, while patients with MASNS show signs of global developmental delay, motor skill deficits, and high pain tolerance. In our work, we found that L50R RIβ stops PKA from going to its destination in cells. We also showed that the MASNS variants slow down or stop PKA from sending important messages to the rest of the cell. These studies highlight different ways in which PKA is controlled in cells and how loss of this control causes disorders in the brain.
Importantly, we now have a better understanding of the role PKA plays in these NLDs. We believe this information can be used to answer further questions and develop treatments for patients with NLPD-PKA or MASNS.
- Academic Unit
- Biomedical Science Program
- Record Identifier
- 9985177075302771
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