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 two 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.

尽管该领域取得了一些进展，但仍迫切需要反映临床生物流体中 LRRK2 激酶活性的药效学结果测量。已经使用了多种目标和方法，包括评估 LRRK2 本身（水平、磷酸化）或其底物（例如 Rab10 或其他 Rab GTPase）。我们之前已经表明，无论疾病状态如何，从 G2019S 携带者的 PBMC 中分离的 LRRK2 的内在激酶活性都会升高。在本研究中，我们发现 Rab10 的磷酸化在 G2019S 携带者中也升高，但仅限于 PD 携带者。此外，该底物的磷酸化在两个独立的特发性 PD 队列中也升高，但在 α-突触核蛋白中 A53T 突变的携带者中没有升高。相比之下，Rab29 磷酸化在 A53T 和特发性 PD 患者的尿外泌体中特异性降低。总之，我们的研究结果强调了评估多个互补目标的必要性，以便更全面地了解该疾病。