ArticleNeurobiology of disease2025
14-3-3θ phosphorylation exacerbates alpha-synuclein aggregation and toxicity.
Article in Neurobiology of disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- 14-3-3θ phosphorylation at S232 reduces its interactome and regulates axonal trafficking.Disease models & mechanisms · 2025Article
- 14-3-3 Proteins Negatively Regulate Microglial Activation via Inhibition of the NF-κB Pathway.Journal of neurochemistry · 2025Article
- A novel 14-3-3θ phosphomimetic mouse model demonstrates social dominance defects.Biology open · 2025Article
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9 authors.
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Abstract
Aggregation of alpha-synuclein (αsyn) plays an integral role in Parkinson's disease (PD) and Dementia with Lewy bodies (DLB). 14-3-3θ is a highly expressed brain protein with chaperone-like activity that regulates αsyn folding. 14-3-3θ overexpression reduces αsyn aggregation, transmission between cells, and neuronal loss, while 14-3-3 inhibition promotes αsyn pathology. We previously observed increased 14-3-3θ phosphorylation at serine 232 in human PD and DLB brains. Here we examine 14-3-3θ phosphorylation's effects on αsyn aggregation and toxicity. Using a paracrine αsyn model, we found that the non-phosphorylatable S232A 14-3-3θ protected while the phosphomimetic S232D 14-3-3θ failed to protect against αsyn paracrine toxicity. The S232A mutant reduced oligomerization of released αsyn while the S232D mutant did not. The S232D mutant showed significant reduction in αsyn binding compared to wildtype or S232A 14-3-3θ. Using knock-in mouse models expressing the S232A or S232D mutation in the cortex and hippocampus, we examined the impact of S232 phosphorylation on αsyn aggregation in the αsyn preformed fibril (PFF) model. Primary neurons from S232D mice showed increased αsyn inclusion formation compared to neurons from Cre control mice upon PFF treatment. In contrast, neurons from S232A mice showed reduced αsyn inclusions. αSyn PFF injection into the dorsolateral striatum induced higher αsyn inclusion numbers in the sensorimotor cortex of S232D mice compared to Cre control mice. In conclusion, 14-3-3θ phosphorylation at S232 interrupts the ability of 14-3-3θ to bind and regulate αsyn aggregation. Increased 14-3-3θ phosphorylation observed in human PD and DLB likely accelerates neurodegeneration in these disorders.
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