Inhibition of TGF-beta signaling protects from alpha-synuclein induced toxicity Article Swipe
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· 2025
· Open Access
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· DOI: https://doi.org/10.1038/s41420-025-02901-2
· OA: W4417305284
Parkinson’s disease (PD) is histopathologically defined by the presence of Lewy bodies, which are intracellular proteinaceous inclusions that contain mainly aggregated alpha-synuclein (aSyn). It is believed that oligomeric intermediates between monomeric aSyn and large aggregates are neurotoxic, which would lead to the demise of dopaminergic neurons. Therefore, novel therapies preventing aSyn-induced cell death need to be developed. Therefore, we performed a genome-wide siRNA screening in an aSyn-induced dopaminergic cell death model and found the knockdown of three transforming growth factor-beta (TGFb) pathway-related genes to be protective. Hence, we hypothesized that a reduction in TGFb signaling would protect dopaminergic neurons from aSyn-induced toxicity. Thus, we validated the results of the genome-wide knockdown screening with the use of two different types of siRNAs. We confirmed that the knockdown of Activin receptor-like kinase 5 ( ALK5 ) and Mothers against decapentaplegic homolog 2 ( SMAD2 ), two genes of the TGFb pathway, protected dopaminergic neurons from aSyn-induced toxicity. An increase in TGFb signaling by treatment with TGFb ligands further exacerbated aSyn-induced toxicity, whereas this effect was mitigated by knockdown of ALK5 , SMAD2 , or Dynein light chain roadblock type-1 ( DYNLRB1 ). Moreover, TGFb ligand treatment induced an up-regulation of SNCA mRNA expression in aSyn-overexpressing cells. Interestingly, consistent with the literature, we identified an up-regulation of the genes of the TGFb pathway in aSyn-overexpressing cells. Altogether, we identified a potential protective role by interference with the TGFb pathway against aSyn-induced toxicity. These findings provide a rationale for the development of novel strategies against PD.
