14-3-3θ phosphorylation exacerbates alpha-synuclein aggregation and toxicity.

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Alpha-synuclein (αsyn) aggregation is central to Parkinson's disease (PD) and Dementia with Lewy bodies (DLB).
• 14-3-3θ protein acts as a chaperone, regulating αsyn folding and aggregation.
• Elevated 14-3-3θ phosphorylation at serine 232 is observed in human PD and DLB brains.

Purpose of the Study:

• To investigate the functional impact of 14-3-3θ phosphorylation at serine 232 on αsyn aggregation and toxicity.
• To determine how specific phosphorylation states of 14-3-3θ affect αsyn binding and pathological processes.

Main Methods:

• Utilized a paracrine αsyn model with non-phosphorylatable (S232A) and phosphomimetic (S232D) 14-3-3θ mutants.
• Employed knock-in mouse models expressing S232A or S232D 14-3-3θ mutations.
• Administered αsyn preformed fibrils (PFFs) to primary neurons and in vivo models.

Main Results:

• The S232A mutant protected against αsyn toxicity and reduced αsyn oligomerization, while the S232D mutant did not.
• S232D 14-3-3θ exhibited reduced binding affinity for αsyn compared to wild-type or S232A.
• Neurons from S232D mice showed increased αsyn inclusion formation upon PFF treatment, unlike S232A mice.

Conclusions:

• Phosphorylation of 14-3-3θ at S232 disrupts its chaperone activity towards αsyn, promoting aggregation.
• The heightened S232 phosphorylation in PD and DLB brains likely exacerbates neurodegeneration by impairing αsyn regulation.