Distinct profiles of LRRK2 activation and Rab GTPase phosphorylation in clinical samples from different PD cohorts

Abstract

Despite several advances in the field, pharmacodynamic outcome measures reflective of LRRK2 kinase activity in clinical biofluids remain urgently needed. A variety of targets and approaches have been utilized including assessments of LRRK2 itself (levels, phosphorylation), or its substrates (e.g. Rab10 or other Rab GTPases). We have previously shown that intrinsic kinase activity of LRRK2 isolated from PBMCs of G2019S carriers is elevated, irrespective of disease status. In the present study we find that phosphorylation of Rab10 is also elevated in G2019S carriers, but only those with PD. Additionally, phosphorylation of this substrate is also elevated in 2 separate idiopathic PD cohorts, but not in carriers of the A53T mutation in α-synuclein. In contrast, Rab29 phosphorylation was specifically reduced in urinary exosomes from A53T and idiopathic PD patients. Taken together, our findings highlight the need for the assessment of multiple complimentary targets for a more comprehensive picture of the disease.

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

“…One of the potential biomarkers currently studied is phospho-Ras-related protein Rab-10 (Rab10). However, although phospho-Rab10 is readily dephosphorylated in patient cells upon LRRK2 inhibition 54,55 , there are conflicting results regarding its ability to differentiate between PD and healthy individuals for example [55][56][57][58] . Moreover, biomarkers are still lacking that would discriminate between PD and atypical parkinsonian disorders.…”

Neuroprotective actions of a fatty acid nitroalkene in Parkinson’s disease.

“…Kinase-activating mutations in the LRRK2 gene are strongly linked with familial PD (64) and contribute to enhanced risk of idiopathic PD (iPD) (63). It is also well established that LRRK2 kinase activation occurs in iPD independent of an activating mutation (16,65,66). The present study reveals that 10-NO2-OA dosedependently limits increases in rotenone-induced LRRK2 kinase activity in dopamine neurons and may represent a central mechanism of action 10-NO2-OA in countering aspects of PD pathogenesis.…”

LRRK2 and idiopathic Parkinson’s disease

“…Elevated phosphorylated Rab10 has been observed in postmortem human brain tissue [7], peripheral immune cells [32], and blood from patients with iPD i . Additionally, preliminary results indicated that elevated phosphorylated Rab10 is present in peripheral blood mononuclear cells (PBMCs) in two cohorts of subjects with iPD [33]. These results suggest there is increased LRRK2 kinase activity or decreased phosphatase activity in iPD.…”