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

## TL;DR

This study shows that blocking TGF-beta signaling can protect neurons from damage caused by alpha-synuclein, a protein linked to Parkinson's disease.

## Contribution

The study identifies TGF-beta pathway inhibition as a novel protective strategy against alpha-synuclein-induced toxicity in Parkinson's disease.

## Key findings

- Knockdown of ALK5 and SMAD2 in the TGFb pathway protected dopaminergic neurons from alpha-synuclein toxicity.
- TGFb ligand treatment worsened alpha-synuclein-induced toxicity, but this was reduced by pathway inhibition.
- TGFb pathway genes were upregulated in alpha-synuclein-overexpressing cells, suggesting a disease-related mechanism.

## 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.