LRRK2 - Fifteen Years From Cloning to the Clinic

In the time since the identification of LRRK2 at the PARK8 locus as the responsible gene mutated in a common autosomal dominantly inherited form of Parkinson’s disease, it has become increasingly evident that activity of this protein plays a crucial role in disease pathogenesis in familial Parkinson’s disease, as well as other forms of the disease. Its phosphorylation of many members of the Rab GTPase family, places LRRK2 in a key role regulating the intracellular trafficking and modification of a rapidly expanding array of proteins, vesicles, and receptors. We are constantly learning more about this aspect of LRRK2 function, in a physiological context; but also within the context of disease pathogenesis. Recent work has yielded two key findings: that LRRK2 activity may also play a major role in multiple forms of PD, not only those associated with mutations in the LRRK2 gene; and secondly, that this activity contributing to the neurodegeneration underlying PD occurs both in neuronal cells as well as non-neuronal cells (e.g. microglia/macrophages, astrocytes, etc.). The selected contributing authors and manuscript topics in the proposed Research Topic will reflect several aspects of these findings.

Common to understanding both its physiological functions, as well as its role in disease pathogenesis, is a characterization of its downstream targets as well as its upstream regulation. Particularly dependent on the cellular type, the regulation of the function of LRRK2, via phosphorylation by other kinases or the coordinated activities of its GTPase domain and auto-phosphorylation events, is extremely complex. Similarly, it is crucial to gain a deeper understanding of the pathways and systems regulated by the kinase activity of LRRK2, not only under physiological conditions but also in the context of disease pathology. This latter issue has attained greater urgency since early Phase I clinical trials of LRRK2 kinase inhibitors, potential therapeutic candidates in PD, have begun. Parallel to this effort, trials of investigational compounds targeting LRRK2 activity must also be accompanied by validated LRRK2 biomarkers. Here, the goal is two-fold: to establish a marker of changes in LRRK2 function that correlate with, or predict, disease progression; and, assays capable of demonstrating target engagement of test compounds. Thus, we will propose several possible entries to this Research Topic that will address these specific areas.

This Research Topic will be comprised of review articles from the leading experts in LRRK2 biology, including representatives from funding organizations as well as industry, covering the latest advances in the following subtopics:

Genetics of LRRK2

LRRK2 function:
Kinase and GTPase activity, where things stand
Structure/conformation and activity
Post-translational modification of LRRK2:
- Ubiquitination/protein turnover (proteasomal, lysosomal)
- Phosphorylation
Signaling pathways regulated by LRRK2
Localization and activity

Implications for disease pathogenesis:
Physiological functions
- Cellular substrates of LRRK2
- Effects of LRRK2 at the synapse
LRRK2 and the immune system/neuroinflammation
LRRK2 signaling in other diseases (IBD, leprosy, cancer)

Clinical considerations of LRRK2-PD:
Clinical presentation of LRRK2 mutation carriers vs other fPD and iPD
Clinical trials of LRRK2 inhibitors
LRRK2-focussed biomarkers