The clinicopathological phenotype of G2019S LRRK2-associated Parkinson’s disease (L2PD) is comparable to that of idiopathic Parkinson’s disease (IPD) and L2NMCs with G2019S LRRK2 are more likely to develop PD. With several treatment methods in the clinical and preclinical pipelines, there was a pressing need to develop biomarkers that can help in early diagnosis and patient enrichment for ongoing and future LRRK2-targeted studies. For a study, researchers sought to examine differential protein and phospho-protein changes in peripheral blood mononuclear cells from G2019S L2PD patients and G2019S L2NMCs, identify specific phospho-protein changes associated with the G2019S mutation and disease status, and compare results to patients with iPD.

They used isobaric label–based mass spectrometry to perform an unbiased phospho-proteomic study on peripheral blood mononuclear cell group pools from an LRRK2 cohort from Spain that included patients with G2019S L2PD (n=20), G2019S L2NMCs (n=20), healthy control subjects (n=30), patients with iPD (n=15), patients with R1441G L2PD (n=5), and R1441G

They discovered phospho-protein alterations linked with the G2019S mutation by comparing G2019S carriers to healthy controls. Furthermore, they discovered a unique G2019S phospho-signature that varied with illness state and may distinguish patients with G2019S L2PD, G2019S L2NMCs, and healthy controls. Although patients with IPD had a varied phospho-proteomic profile, biological enrichment studies revealed that the three groups had similar alterations in deregulated pathways. They discovered a distinct phospho-signature linked with LRRK2 G2019S, and the phospho-profile from PD at-risk G2019S L2NMCs was more comparable to healthy controls than patients with G2019S L2PD with manifested illness.