Rideout Hardy J, Chartier-Harlin Marie-Christine, Fell Matthew J, Hirst Warren D, Huntwork-Rodriguez Sarah, Leyns Cheryl E G, Mabrouk Omar S, Taymans Jean-Marc
Division of Basic Neurosciences, Biomedical Research Foundation, Academy of Athens, Athens, Greece.
Univ. Lille, Inserm, CHU Lille, U1172 - Lille Neuroscience & Cognition, Lille, France.
Front Neurosci. 2020 Aug 18;14:865. doi: 10.3389/fnins.2020.00865. eCollection 2020.
Evidence is mounting that LRRK2 function, particularly its kinase activity, is elevated in multiple forms of Parkinson's disease, both idiopathic as well as familial forms linked to mutations in the gene. However, sensitive quantitative markers of LRRK2 activation in clinical samples remain at the early stages of development. There are several measures of LRRK2 activity that could potentially be used in longitudinal studies of disease progression, as inclusion/exclusion criteria for clinical trials, to predict response to therapy, or as markers of target engagement. Among these are levels of LRRK2, phosphorylation of LRRK2 itself, either by other kinases or via auto-phosphorylation, its kinase activity, or phosphorylation of downstream substrates. This is advantageous on many levels, in that multiple indices of elevated kinase activity clearly strengthen the rationale for targeting this kinase with novel therapeutic candidates, and provide alternate markers of activation in certain tissues or biofluids for which specific measures are not detectable. However, this can also complicate interpretation of findings from different studies using disparate measures. In this review we discuss the current state of LRRK2-focused biomarkers, the advantages and disadvantages of the current pallet of outcome measures, the gaps that need to be addressed, and the priorities that the field has defined.
越来越多的证据表明，在多种形式的帕金森病中，包括特发性帕金森病以及与该基因突变相关的家族性帕金森病中，LRRK2的功能，尤其是其激酶活性均有所升高。然而，临床样本中LRRK2激活的敏感定量标志物仍处于研发的早期阶段。有几种LRRK2活性的检测方法有可能用于疾病进展的纵向研究、作为临床试验的纳入/排除标准、预测治疗反应或作为靶点参与的标志物。其中包括LRRK2的水平、LRRK2自身被其他激酶磷酸化或通过自磷酸化的磷酸化水平、其激酶活性或下游底物的磷酸化水平。这在多个层面上具有优势，因为激酶活性升高的多个指标显然加强了用新型治疗候选物靶向该激酶的理论依据，并为某些无法检测到特定指标的组织或生物流体提供了激活的替代标志物。然而，这也可能使使用不同检测方法的不同研究结果的解释变得复杂。在这篇综述中，我们讨论了以LRRK2为重点的生物标志物的现状、当前结果测量方法的优缺点、需要解决的差距以及该领域已确定的优先事项。
