Advisor(s)
Briana De Miranda
Talene Yacoubian
Committee Member(s)
Laura Volpicelli-Daley
Matthew Goldberg
William Marsiglia
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Neurobiology
Date of Award
9-11-2025
Abstract
14-3-3s are a family of proteins highly expressed in the brain. These proteins exert their functions mainly through protein-protein interactions (PPIs) and have thousands of binding partners. 14-3-3s have been shown to be present in pro-teinaceous aggregates of alpha-synuclein (αsyn), a pathological hallmark of synucleinopathies. This includes such diseases as Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). 14-3-3 proteins, particularly the 14-3-3θ isoform, have been shown to be protective in multiple synucleinopathy models. However, reduced soluble levels of 14-3-3s and increased phosphorylation of 14-3-3θ at S232 observed in synucleinopathies like DLB may impair their protec-tive ability, potentially due to disruptions in their PPIs. In this study, we investigated how these PPIs change and how these changes affect axonal trafficking. In cortical samples from patients with PD and DLB there is an observed increase in S232 phosphorylation which has been shown to im-pair 14-3-3θ’s interaction with αsyn. We compared the cortical interactome of 14-3-3θ in a phospho-mimetic S232D knock-in mouse to a phospho-deficient S232A knock-in mouse and found S232D had a significantly reduced 14-3-3θ interactome compared to S232A. These proteins with reduced 14-3-3θ interac-tions had numerous functions, but one notable one was axonal transport. We then examined the interactome of 14-3-3θ in DLB and healthy age-matched controls and found significant differences in certain proteins, such as axonal transport proteins and tau. 14-3-3s regulate axonal transport and disease-relevant disruptions to 14-3-3θ’s interactome reduced interactions with several axonal transport proteins. We ex-amined how disease-associated 14-3-3 modifications affect axonal transport. Utilizing our S232 phospho-mutant mice, we found dysregulation of S232’s phosphorylation status caused retrograde and anterograde deficits in acidic ves-icle axonal trafficking. In a functional 14-3-3 knock-out (difopein) primary neu-ron model mimicking reduced 14-3-3 solubility in DLB, we examined axonal traf-ficking of mitochondria and lysosomes. We found anterograde defects in lyso-some trafficking and profound retrograde defects in mitochondria. Impaired traf-ficking of these organelles is detrimental to neuron function and could contrib-ute to neurodegeneration. These data indicate that 14-3-3 PPIs are disrupted in synucleinopathies, caus-ing impairment of critical biological functions such as axonal trafficking. These proteins warrant further research as novel therapeutic targets.
ProQuest ID
Recommended Citation
Pair, Frank Sanders, "Murder On The Axonal Express: Synucleinopathy Disruption Of 14-3-3 Protein-Protein Interactions Impairs Axonal Trafficking" (2025). All ETDs from UAB. 7429.
https://digitalcommons.library.uab.edu/etd-collection/7429
