Proteomic analysis reveals complex interactions between PERK/ISR and MAPK1 in translational control in a phenotypic toxin model of Parkinson’s disease expressing PINTAC peptides

In a proteomics investigation of a Parkinson’s disease [PD] cell model, a panel of 7 proprietary PINTAC peptides deployed in an in vitro phenotypic screen in SH-SY5Y cells treated with 6-OHDA identified 2 shorter variants of PERK protein kinase. One of the PERK variants, which is SUMOylated, associates in vitro with phosphorylated EIF2 alpha and its ubiquitinated isoforms, which also involves another PERK substrate. PINTACs revealed the presence of multiple post-translational modifications [PTMs] of MAPK1 in presence of OHDA. A fragment derived from MAPK1 protein sequence physically associated with multiple proteins from SH-SY5Y cells in vitro , including some PERK substrates involved in translational control. Most associations were abolished by OHDA treatment, with concomitant appearance of new interactions of the MAPK1 peptide with RSK proteins. Some PINTACs promoted the potentiation of the function of RPS6 via RSK activation induced by OHDA. A model of the phenotypic effects of aggregator and degrader PINTAC peptides is presented. The significance of these findings for novel drug discovery in PD is discussed in the context of target discovery and therapeutic applications of PINTAC peptides or small molecule mimics.