Regulators of proteostasis are translationally repressed in fibroblasts from sporadic and LRRK2-G2019S Parkinson's patients

Abstract

Parkinsons disease (PD) is characterized by heterogeneous motor and non-motor symptoms. The majority of PD cases are sporadic, whereas the leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is the most common monogenic cause of familial PD and symptomatically indistinguishable from the sporadic form. Deficits in protein synthesis have been reported in PD. However, it is not known which proteins are affected or if there are synthesis differences between patients with sporadic and LRRK2 G2019S PD. Here we used non-canonical amino acid labeling and mass-spectrometry based proteomics to perform a quantitative comparison of nascent proteins in fibroblasts from sporadic and G2019S mutation PD patients compared to healthy individuals. We found that several proteins were under-represented among nascent proteins in cells from PD patients. Among these were regulators endo-lysosomal sorting, mRNA processing and translation itself. We further validated which of these proteins were dysregulated at the static proteome level using targeted proteomics. Key downregulated proteins included the autophagy regulator ATG9A and translational stability regulator YTHDF3. Notably, 68% of the identified proteins were downregulated in both sporadic and LRRK2-G2019S forms of PD. We identify translational repression of key regulators of proteostasis in patient fibroblasts that are common to both sporadic and LRRK2-G2019S PD.