Objective: This study aims to explore the impact of the A53T alpha-synuclein (α-syn) mutation on astrocytic homeostasis and metabolism in the presence of inflammatory stimuli.

Background: Alpha-synuclein (α-syn) is a presynaptic protein highly expressed in the brain. Its aggregated forms are the main component of Lewy bodies, which are found in the brains of most Parkinson’s Disease (PD) patients, even in the absence of mutations in the SNCA gene itself. While the effect of mutant α-syn has mostly been studied in dopaminergic neurons, recent studies highlight the role of glial cells in the pathogenesis of PD. Astrocytes, the most abundant glial cells in the brain, provide crucial metabolic support to neurons, yet the role of SNCA mutations in this cell type remains understudied. We hypothesize that the A53T mutation in α-syn disrupts astrocytic metabolism, thus impairing their capacity to respond to inflammatory stimuli.

Method: To investigate this, we stimulated iPSC-derived astrocytes from both healthy individuals and A53T mutation carriers with cytokines, including IL-1β and TNF-α, and performed OMICs and imaging analyses.

Results: Immunostaining confirmed the expression of specific astrocytic markers in both cultures, while in terms of morphology, the A53T astrocytes appeared more ameboid, suggestive of altered activation. Transcriptomic analysis revealed genotype-specific differences in metabolic pathways under basal conditions, which are further supported by our metabolomics data. Cytokine activation exacerbated these metabolic differences, while also triggering distinct inflammatory signaling patterns. Finally, mitochondrial function assays showed a decrease in the mitochondrial mass and the membrane potential upon activation, regardless of the genotype, with a trend for higher maximal and spare respiratory capacity in the A53T α-syn cells.

Conclusion: Taken together, our data suggests that the A53T α-syn mutation interferes with the neuronal support function of astrocytes, which could in turn contribute to the neuronal demise occurring in PD. These findings advance the current knowledge about glial dysfunction in PD pathology, highlighting astrocytes as new potential therapeutic targets.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-a53t-mutation-in-alpha-synuclein-impairs-astrocytic-metabolism-and-inflammatory-response/