LRRK2 (leucine-rich repeat kinase 2) is a gene of unknown function that has been linked to a number a human diseases, including PD (Parkinson's disease), IBD (inflammatory bowel disease), leprosy and cancer. The papers from the LRRK2: Function and Dysfunction meeting in this issue of Biochemical Society Transactions explore our growing knowledge of LRRK2's normal function, the role that it plays in disease and emerging strategies to exploit LRRK2 as a therapeutic target.

Introduction

Of all the genes that have been linked to PD (Parkinson's disease), the LRRK2 (leucine-rich repeat kinase 2) gene (also known as PARK8), has generated perhaps the most direct interest as a putative therapeutic target. Interest in this gene was first stimulated by the discovery in 2004 of point mutations in LRRK2 that were causative for autosomal dominant PD [1,2]. Since 2004, we have learned a huge amount about the genetics of LRRK2 and the biology of LRRK2, the protein product. It has become clear that mutations in LRRK2 are the most common genetic cause of PD and, more recently, that common variation at the LRRK2 locus can increase the risk of developing the sporadic form of the disease [36], providing a concrete link between the Mendelian mutations and idiopathic disease. With regard to the cellular function and biology of LRRK2, a picture is emerging of an intimate relationship between the enzymatic functions of this protein and cell death in the presence of mutations, although the exact pathways through which this occurs remain a mystery [7].

LRRK2: a hydra with heads in many diseases

Intriguingly, evidence is building to support a multifactorial role for LRRK2 in a number of human disease, ranging from PD, through Crohn's disease to leprosy and cancer [810]. How the biology of LRRK2 interplays with the aetiology of these disorders, and whether these links represent opposing or congruent roles for LRRK2 is, as yet, unclear [11]. Untangling this Gordian knot is likely to have important implications for LRRK2 as a therapeutic target, for, if there are opposing activities involved, cutting off one head of the Hydra by inhibiting kinase activity, for example, may result in another growing back in a different disorder (Figure 1).

LRRK2 as the Lernaean Hydra, the mythical multi-headed monster that, for every head that was cut off, two grew back

Figure 1
LRRK2 as the Lernaean Hydra, the mythical multi-headed monster that, for every head that was cut off, two grew back

LRRK2s involvement in multiple diseases may make it as challenging an opponent as the Hydra. Woodcut from Edward Topsell's History of Four-footed Beasts and Serpents (1658).

Figure 1
LRRK2 as the Lernaean Hydra, the mythical multi-headed monster that, for every head that was cut off, two grew back

LRRK2s involvement in multiple diseases may make it as challenging an opponent as the Hydra. Woodcut from Edward Topsell's History of Four-footed Beasts and Serpents (1658).

Progress on the road to a holistic view of LRRK2 function

It is in the context of an ever-increasing volume of research into the biology of LRRK2 that the Biochemical Society Focused Meeting LRRK2: Function and Dysfunction was held at Royal Holloway in March 2012. In this issue of Biochemical Society Transactions, the leading researchers in the LRRK2 field report on some of the exciting discoveries from the last several years.

Central to these advances has been the development of tools with which to identify and manipulate LRRK2, and model systems that allow careful dissection of its cellular function. These range from inhibitors that target LRRK2's kinase function [12,13], antibodies specific for LRRK2 and some of its key phosphorylation sites [14], to mouse, fruitfly and human cell models (see, for example, [1517]). One of the driving forces behind the development of the tools and models over the last three years has been the formation of the Michael J. Fox Foundation LRRK2 consortium (http://www.michaeljfox.org/foundation/publication-detail.html?id=253&category=4), which has brought together investigators from all over the world in order to accelerate LRRK2 research.

There have been a number of important advances in the preceding 12 months, some of which are covered in greater detail in this issue of Biochemical Society Transactions. These include the first data showing a functional link between LRRK2 and the aetiology of IBD (inflammatory bowel disease) [18], the first structure for a kinase domain from a leucine-rich repeat kinase [19] and data revealing a key role for LRRK2 in glial cells and inflammatory response [20]. It is a tribute to the hyperactivity of researchers in the LRRK2 field that these are only the tip of the iceberg; a cursory glance at PubMed reveals over 850 publications relating to LRRK2 as of July 2012, with over 80 since the start of the year.

The goals of LRRK2 research over the next several years

Despite the major strides that have been made in understanding LRRK2 function, there remain many questions that need to be addressed before we have a clear idea as to how dysfunction in LRRK2 leads to nigral cell death and thereby PD, let alone clarifying the role of LRRK2 in IBD, cancer and leprosy.

One of the key questions that needs to be addressed is what the genome-wide associations linking LRRK2 to PD, IBD and leprosy actually mean. Currently, we know that there is increased risk for each of these disorders linked to the genomic region within which LRRK2 sits, and we are becoming increasingly confident that this signal relates to LRRK2 itself. The biological alteration underpinning this association, however, remains to be determined in all three cases. Is the signal a marker for increased or decreased LRRK2 expression? Or does the association relate to altered splicing of LRRK2? Elucidating the biological nature of these associations will be a major step forward in understanding LRRK2's involvement in disease. Following from this, the link between LRRK2 and cancer is equally clouded [21], and again much work remains to be done to clarify this relationship.

One fundamental question that remains unanswered is how PD-linked mutations in LRRK2 can lead to different neuropathological outcomes, ranging from α-synuclein inclusions to tau and TDP-43 (TAR DNA-binding protein 43) pathologies [2,22]. There is no obvious segregation of specific mutations with a particular pathology, and indeed sometimes individuals within the same family, carrying the same mutation on a closely related genetic background, display divergent pathologies. This highlights important issues around the correlation of genotype, clinical phenotype and pathology, but, aside from those issues, the suspicion persists that if we understand the basis for the pleomorphic pathology in LRRK2 PD cases, we will have made a great leap forward in our comprehension of LRRK2 function.

At a molecular level, there is still a gap in our knowledge as to how the various domains of LRRK2 relate to one another, although, as with much of LRRK2's biology, this is proving to be more complicated than it first appeared; for example, there appears to be an interplay between the C-terminal WD40 domain of LRRK2 and kinase activity [23,24]. One of the critical pieces required for completion of this puzzle will be structural data revealing the spatial and functional relationship between the kinase and GTPase domains of LRRK2, and, although progress has been made in this direction [25], we are still a long way short of a crystal structure for LRRK2. Building from a crystal structure for LRRK2, it is also essential that we begin to identify splice variants for LRRK2 and how these might alter function, as well as a fuller picture of physiologically relevant binding partners and potential substrates. This, in turn, will yield valuable insights into the pathways that LRRK2 regulates and perhaps inform us as to whether other aspects of LRRK2 biology in addition to its kinase activity can be targeted [26].

Important steps have been made in understanding the function of LRRK2, and the roles that it plays in a number of human diseases. Much, however, remains to be discerned as to the precise nature of its dysfunction in Parkinson's and a range of other human diseases. What is certain is that the next several years promise to be an exciting time for research into this enigmatic gene.

LRRK2: Function and Dysfunction: A Biochemical Society Focused Meeting held at Royal Holloway, University of London, Egham, UK, 28–30 March 2012. Organized and Edited by Patrick Lewis (University College London, U.K.) and Dario Alessi (Dundee, U.K.).

Abbreviations

     
  • IBD

    inflammatory bowel disease

  •  
  • LRRK2

    leucine-rich repeat kinase 2

  •  
  • PD

    Parkinson's disease

We thank all of the attendees of the Biochemical Society Focused Meeting LRRK2: Function and Dysfunction and in particular those who presented data at the meeting and have contributed to this issue of Biochemical Society Transactions. The meeting was partly sponsored by Parkinson's UK, Alzheimer's Research UK, Eisai Pharmaceuticals, Boehringer Ingelheim and Pfizer. We extend special thanks to Beth Faircliffe at the Biochemical Society for her efforts in ensuring that the meeting went as smoothly as it did.

Funding

P.A.L. is a Parkinson's UK research fellow [fellowship F1002] and thanks Parkinson's UK and the Michael J. Fox Foundation for generous research support. D.R.A. thanks the Medical Research Council, Parkinson's UK and the Michael J. Fox Foundation for support. Research in both of our laboratories is supported in part by the Wellcome Trust–Medical Research Council Joint Call in Neurodegeneration award [grant number WT089698] to the UK Parkinson's Disease Consortium (UKPDC) whose members are from the UCL Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee.

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Author notes

1

This article is dedicated to the memory of Rhys Thomas Lewis (1903–2012).