Proline repeats, in cis- and trans-positions, confer protection against the toxicity of misfolded proteins in a mammalian cellular model

A broad range of neurodegenerative disorders result from the cytotoxicity conferred by aberrantly folded mutant proteins. Intriguingly, the cytotoxicity and aggregation property of a few mutant proteins are known to be modulated by the flanking sequences. One of such modulators is the proline repeat tract. Using a mammalian cellular model, we show here that proline repeat tract, both in cis- and in trans-positions, ameliorate the cytotoxicity of wide range of misfolded proteins coded by synthetic constructs. We further show that the proline repeat tract could possibly confer protection against the cytotoxicity of misfolded proteins by altering their conformation at the time of their synthesis. Thus, our study elucidates the mechanism by which the proline repeat tract might ameliorate the toxicity of misfolded proteins, and opens up new therapeutic modalities for disorders caused by cytotoxic misfolded proteins.

► Proline repeat tract reduces the cytotoxicity of misfolded protein when present in the same peptide (cis-effect). ► Proline repeat tract reduces the cytotoxicity of misfolded protein when coexpressed (trans-effect). ► Proline repeat tracts rescue cells from the toxicity of aggregate-prone proteins possibly by preventing their misfolding into a cytotoxic form.