The Parkinson's disease-associated A53E mutation decreases alpha-synuclein aggregation and phosphorylation in vivo

A53E mutant alpha-synuclein in vivo remains significantly more mobile than E46K or wild-type, and it lacks detectable serine-129 phosphorylation.

• Why it matters: Understanding how rare alpha-synuclein mutations alter aggregation and phosphorylation in living systems is key to explaining why in vitro fibrillization effects do not straightforwardly predict Parkinson’s disease severity.
• What they did: Using fluorescence recovery after photobleaching in presynaptic terminals, the authors tracked mobility over days for A53E, E46K, and wild-type alpha-synuclein, then tested causality by engineering A53E to mimic S129 phosphorylation.
• The result: E46K and wild-type progressively lose mobility, whereas A53E maintains high mobility, and adding S129 phosphorylation mimic decreases A53E mobility, implicating serine-129 phosphorylation status in aggregation-linked dynamics.

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