Inhibition of TGF-beta signaling protects from alpha-synuclein induced toxicity

Chua, Oscar Wing Ho; Duan, Linghan; Bothe, Svenja Hanna; Evsyukov, Valentin; Moebius, Claudia; Bickle, Marc; Höglinger, Günter U. und Höllerhage, Matthias (2026): Inhibition of TGF-beta signaling protects from alpha-synuclein induced toxicity. In: Cell Death Discovery, Vol. 12, 44

Abstract

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.

• Item Type: Journal article
• Faculties: Medicine > Munich Cluster for Systems Neurology (SyNergy); Medicine > Medical Center of the University of Munich > Neurological Clinic and Polyclinic with Friedrich Baur Institute
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 2058-7716
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390874280