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 LRRK2 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 in vitro 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.

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by prominent degeneration of dopaminergic neurons in the substantia nigra and aggregation of the protein α-synuclein within intraneuronal inclusions known as Lewy bodies. Ninety percent of PD cases are idiopathic while the remaining 10% are associated with gene mutations that affect cellular functions ranging from kinase activity to mitochondrial quality control, hinting at a multifactorial disease process. Mutations in LRRK2 and SNCA (the gene coding for α-synuclein) cause monogenic forms of autosomal dominant PD, and polymorphisms in either gene are also associated with increased risk of idiopathic PD. Although Lewy bodies are a defining neuropathological feature of PD, an appreciable subset of patients with LRRK2 mutations present with a clinical phenotype indistinguishable from idiopathic PD but lack Lewy pathology at autopsy, suggesting that LRRK2-mediated PD may occur independently of α-synuclein aggregation. Here, we examine whether LRRK2 and α-synuclein, as mediators of neurodegeneration in PD, exist in common or distinct pathways. Specifically, we review evidence from preclinical models and human neuropathological studies examining interactions between the two proteins. Elucidating the degree of interplay between LRRK2 and α-synuclein will be necessary for treatment stratification once effective targeted disease-modifying therapies are developed.

The leucine-rich repeat kinase 2 (LRRK2), the most common causative gene for autosomal-dominant familial Parkinson’s disease, encodes a large protein kinase harboring multiple characteristic domains. LRRK2 phosphorylates a set of Rab GTPases in cells, which is enhanced by the Parkinson-associated LRRK2 mutations. Accumulating evidence suggests that LRRK2 regulates intracellular vesicle trafficking and organelle maintenance including Golgi, endosomes and lysosomes. Furthermore, genetic knockout or inhibition of LRRK2 cause lysosomal abnormalities in rodents and primates, and cells from Parkinson’s patients with LRRK2 mutations also exhibit altered lysosome morphology. Cell biological studies on LRRK2 in a diverse cellular context further strengthen the potential connection between LRRK2 and regulation of the endolysosomal system, part of which is mediated by Rab phosphorylation by LRRK2. We will focus on the latest advances on the role of LRRK2 and Rab in relation to the endolysosomal system, and discuss the possible link to the pathomechanism of Parkinson’s disease.