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A Dual Assay to Compare Protein Levels and Toxicity of Alpha-Synuclein Variants: Acute Expression of Wild-Type versus S129A

Li, B.; Levy, O. A.; Ramalingam, N.; Dettmer, U.

2025-09-28 cell biology
10.1101/2025.09.23.678012 bioRxiv
Show abstract

Parkinsons disease (PD) affects over 12 million people worldwide and has the fastest-growing global impact. The pathological hallmark is the presence of Lewy bodies and Lewy neurites, which are intraneuronal lesions enriched in aggregated alpha-synuclein (S) that is typically hyper-phosphorylated at serine 129. Therefore, lowering phosphoserine 129 (pS129) may be a viable therapeutic strategy to treat PD. However, pS129 has also been proposed to regulate synaptic transmission and S degradation. In both cases, inhibiting pS129 could be detrimental. Here, we developed a sensitive assay in a human neuroblastoma model and utilized it to assess the relative expression levels and cytotoxicity of pS129 by comparing S wild-type (WT) vs. S129A (pS129-deficient). We show that the S129A mutant does not affect the acute expression levels or toxicity of S in a transient transfection paradigm. This provides new insight into the intricate interplay between S, phosphorylation, toxicity, and degradation. Our assay provides a versatile platform for understanding disease-relevant mechanisms and opens novel avenues for the design of future therapeutic interventions in PD and other -synucleinopathies.

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