LRRK2 in Parkinson's disease: protein domains and functional insights

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Parkinson's disease (PD) is the most common motor neurodegenerative disease. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) have been linked recently with autosomal-dominant parkinsonism that is clinically indistinguishable from typical, idiopathic, late-onset PD. Thus, the protein LRRK2 has emerged as a promising therapeutic target for treatment of PD. LRRK2 is extraordinarily large and complex, with multiple enzymatic and protein-interaction domains, each of which is targeted by pathogenic mutations in familial PD. This review places the PD-associated mutations of LRRK2 in a structural and functional framework, with the ultimate aim of deciphering the molecular basis of LRRK2-associated pathogenesis. This, in turn, should advance our understanding and treatment of familial and idiopathic PD.

Introduction

Parkinson's disease (PD) is a common and cruelly debilitating neurodegenerative disease characterized by tremor, rigidity, bradykinesia and postural instability. Typical of multifactorial diseases, the incidence of PD increases with age, with an estimated 0.3% afflicted at age 50 increasing to 4.3% by age of 85 [1]. PD is incurable and characterized pathologically by the progressive loss of dopaminergic neurons from the substantia nigra pars compacta and the presence of intracellular Lewy bodies in surviving neurons of the brainstem [2]. Although a common unifying cause of PD at the cellular level has not been identified, the culprits might include the formation of cellular aggregates and dysfunction of protein clearance mechanisms, oxidative stress leading to mitochondrial dysfunction and apoptosis, and/or defects in cellular trafficking [3]. There are genetic findings to support each of these theories.

To develop better treatments for PD, it is necessary to identify and therapeutically exploit key molecules involved in the pathogenic process. Mutations in several genes have been genetically linked to PD in recent years [4]. Although these key discoveries in human genetics promise to catalyze our molecular and cellular understanding of PD, mutations in most PD-associated genes have been correlated with early-onset or pathologically atypical forms of the disease. By contrast, the most recently identified PD-associated gene, encoding leucine-rich repeat kinase 2 (LRRK2), has been associated with late-onset PD 5, 6. Because the clinical phenotype ensuing from LRRK2 mutations resembles idiopathic PD, LRRK2 has emerged as, perhaps, the most relevant player in PD pathogenesis identified to date [7]. Here, we review the state of knowledge with regard to PD-associated amino acid substitutions of LRRK2, placing them in the context of structural domains, and we discuss the potential of LRRK2 as a therapeutic target for the treatment of PD.

Section snippets

LRRK2 – a master regulator gone awry in Parkinson's disease?

Multiple lines of evidence suggest that LRRK2 is key to understanding the etiology of PD. Thus far, at least 20 LRRK2 mutations (Figure 1, Table 1) have been linked to autosomal-dominant parkinsonism 8, 9, 10, accounting for ∼7% of familial PD and for a significant fraction of sporadic PD cases 10, 11, 12. The most prevalent LRRK2 amino acid substitution, G2019S, is responsible for ∼40% of familial and sporadic PD in Arab samples from North Africa 13, 14, ∼30% of familial PD in Ashkenazi Jewish

LRRK2 – a multidomain, multifunctional protein

The LRRK2 gene contains 51 exons and its encoded protein is unusually large (2527 amino acids). LRRK2 mRNA is expressed throughout the brain and other organs [6], with in situ hybridization in mice revealing expression predominantly within regions of the basal ganglia that are associated with motor dysfunction in PD, and within non-motor areas such as the hippocampus 23, 24. The LRRK2 paralog LRRK1 encodes a large protein (2052 amino acids) that has an identical domain organization to that of

One protein, two enzymes

LRRK2 and the related LRRK1 are unusual in that they each encode two distinct enzymes – a protein kinase and a putative GTPase – within a single polypeptide chain. Because these two activities might be linked functionally we cover them both in this section, beginning with the kinase domain.

In catalytic domains of protein kinases, a small N-terminal lobe and a larger C-terminal lobe are connected by a hinge-like region to form a cleft in which Mg2+-ATP and the protein substrate bind (Figure 2a).

LRRK2 protein-interaction domains and PD-associated mutations

LRRK2 contains multiple sets of internal repeats, each of which is predicted to adopt a distinct structure. Such repeats, which occur in 14% of all prokaryotic and eukaryotic proteins [57], commonly serve as platforms for protein interactions [28]. The N-terminal region of LRRK2 contains seven predicted ankyrin repeats, each of which forms two antiparallel helices followed by a β-hairpin or loop (Figure 3a). The repeats stack together to form a gently curved structure in the ankyrin repeat

Concluding remarks

Identification of mutations in LRRK2 that cause autosomal-dominant parkinsonism closely resembling idiopathic disease represents a new chapter in PD research. Pleomorphic pathology associated with mutations places LRRK2 further upstream in the cascade of disease pathogenesis than proteins encoded by genes previously linked to parkinsonism. Therapeutic strategies directed against this protein, to slow or even halt disease progression, might be applicable to a broad spectrum of PD and related

Acknowledgements

This work is supported by grants from the National Parkinson's Disease Foundation (J.P.T.) and NIEHS ES13941 (M.F.) and NINDS P01 NS40256 Udall Center (M.F.). K.A.G. acknowledges the American Cancer Society and the estate of Lela M. Soulby for support of her laboratory's work on MLK3, which has helped to shape our thinking about LRRK2. We thank the reviewers for their constructive suggestions. We apologize to authors whose work was not cited owing to space constraints. K.A.G. thanks members of

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