DeGiosio, Rebecca
(2024)
Functional Effects of Schizophrenia-Associated MAP2 Phosphorylation Events.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Microtubules (MTs) support myriad aspects of neuromorphological development, which is thought to be altered in schizophrenia (SZ). Microtubule-associated protein 2 (MAP2) is a prominent regulator of neuronal MT assembly and organization. Diminished immunoreactivity (IR) of this protein has been repeatedly described in post-mortem brain tissue from individuals with SZ, and recent evidence has further established that its phosphorylation state is altered in disorder, with consequence for protein function. This dissertation describes a collection of studies intended to further illuminate the scope of SZ-associated MAP2 pathology and its potential downstream consequences. Chapter 2 details an immunohistochemical experiment using postmortem brain tissue from a matched cohort of SZ and non-psychiatric comparison subjects (N = 20 pairs), examining MAP2-IR in multiple cortical regions distributed across the rostral-caudal axis. This experiment reveals that MAP2-IR deficits are conserved across cortex within-subject, bearing implications for future study and treatment of MAP2 pathology. Chapter 3, using phosphomimetic MAP2C constructs, demonstrates that a subset of SZ-associated MAP2 phosphorylation events can influence MT- and actin-binding affinity as well as MT assembly kinetics in a domain-specific manner; mutants of the proline-rich domain show suppressed MT assembly and actin-binding while maintaining MT-binding, while C-terminal domain mutants additionally have reduced MT-binding capacity. Further, the C-terminal domain mutant S426E- but not the proline-rich domain mutant T293E- has a reduced capacity for process formation upon overexpression in heterologous cells relative to wild-type protein. Finally, Chapter 4 examines the effects of phosphomimetic MAP2B mutations on MT organization/stability in heterologous HEK293T cells as well as dendritic morphology of cultured cortical neurons. I find that C-terminal domain mutants S1782E and S1799D surprisingly confer increased resistance to katanin-mediated MT severing, while the proline-rich domain mutant T1649E augments basilar dendritic arborization in mature neurons. Together, these findings indicate that SZ-associated MAP2 dysregulation is a global phenomenon within-subject, and that phosphorylation of SZ-associated sites in the proline-rich or C-terminal domains of MAP2 differentially regulate its function, with distinct consequences for cellular morphogenesis.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
16 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
20 September 2023 |
| Approval Date: |
16 September 2024 |
| Submission Date: |
26 September 2023 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
174 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Neurobiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
schizophrenia, cytoskeleton, MAP2, microtubule, actin, immunoreactivity, neuromorphology |
| Date Deposited: |
16 Sep 2024 18:52 |
| Last Modified: |
16 Sep 2024 18:52 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45419 |
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