Unexpected Implication of SRP and AGO2 in Parkinson's Disease: Involvement in Alpha-Synuclein Biogenesis

Parkinson's disease (PD) is a neurodegenerative disorder classified by the loss of dopaminergic neurons in the substantia nigra pars compacta, the region of the brain that is responsible for motor control. Surviving neurons in this region contain aggregated protein alpha-Synuclein (alpha Syn) in the form of cytoplasmic inclusions, referred to as Lewy bodies. Changes in alpha Syn expression are also associated with PD and its progression. Previously, we demonstrated that signal recognition particle (SRP) and Argonaute 2 (AGO2) proteins are involved in protein quality control at the ribosome during translation. We also demonstrated that SRP has an mRNA protection function in addition to a protein targeting function, thus controlling mRNA and protein expression. In this study, we tested involvement of these factors in alpha Syn biogenesis. We hypothesize that loss of these factors may interfere with alpha Syn expression, and subsequently, be associated with PD. Using depletion assays in human cell culture and analysis of these proteins in the brains of deceased PD patients, we demonstrate that SRP and AGO2 are involved in the control of alpha Syn expression and AGO2 has reduced expression in PD. We show for the first time that SRP is involved in mRNA protection of alpha Syn, a protein that does not have a signal sequence or transmembrane span. Our findings suggest that SRP may interact with a hydrophobic domain in the middle of alpha Syn during translation. Understanding the molecular mechanisms controlling alpha Syn biogenesis in cells is vital to developing preventative therapies against PD.

Automated summary

The study found that SRP and AGO2 proteins are involved in the control of alpha Syn expression in PD, with reduced expression of AGO2 in PD. SRP was shown for the first time to be involved in mRNA protection of alpha Syn, revealing the potential roles of these factors in the pathogenesis of PD.