Chapter 7 - LRRK2 and Parkinson's Disease

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Leucine-rich repeat kinase-2 (LRRK2) comprises 51 exons and is expressed in most brain regions, including the striatum and substantia nigra (dopamine-receptive areas), cortex, hippo­campus, and subventricular zone. The LRRK2 transcript encodes a 2527-amino acid protein (denoted Lrrk2) that contains several conserved domains, including ankyrin (ANK), leucine-rich repeat (LRR), GTPase (Roc), C-terminal of Roc spacer (COR), mitogen-activated protein kinase (MAPK), and WD40 repeats. The chapter presents a parsimonious model of the way in which genetically proven pathogenic mutations throughout Lrrk2 may affect its function. A cross-sectional and longitudinal evaluation of LRRK2 mutation carriers, including asymptomatic and affected subjects, provides fundamental insight into the natural history of Parkinson's disease (PD) and other contributing environmental and genetic factors. The chapter discusses the LRRK2 protein structure, LRRK2 pathogenic mutations and polymorphic risk factors, LRRK2 pleomorphic pathology, LRRK2 functional neuroscience, and the parsimonious molecular model of LRRK2 activity.

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PARK8 and LRRK2

The PARK8 linkage assignment (locus) was originally mapped to chromosome 12q12 in a Japanese family with asymmetric levodopa-responsive late-onset parkinsonism, consistent with a diagnosis of sporadic Parkinson's disease (PD).1 Confirmation of the PARK8 locus came from Families A and D, which also have autosomal dominant late-onset parkinsonism.2 Sequence analysis subsequently discovered the leucine-rich repeat kinase 2 gene (LRRK2) and disease-segregating R1441C and Y1699C coding substitutions.

Lrrk2 Protein Structure

The LRRK2 transcript encodes a 2527-amino acid protein (denoted Lrrk2), which contains several conserved domains, including ankyrin (ANK), leucine-rich repeat (LRR), GTPase (Roc), C-terminal of Roc spacer (COR), mitogen-activated protein kinase (MAPK), and WD40 repeats.15 Each domain is potentially involved in multiple functions, including substrate binding, protein phosphorylation, and protein-protein interactions.16., 17., 18. The combination of Roc-COR-MAPK motifs, encoding two distinct but

Lrrk2 Pathogenic Mutations and Polymorphic Risk Factors—Families and Founders

More than 75 Lrrk2 missense or nonsense mutations have been described30., 31., 32. (see www.genetests.org), but genetic evidence for pathogenicity is proven only for R1441C/G, Y1699C, G2019S, and I2020T substitutions (by linkage)3., 5., 6., 7. and for Lrrk2 R1628P and G2385R (by association).33., 34., 35., 36., 37., 38. Although other sequence variants may be pathogenic, they might also represent benign mutations or polymorphisms. This is an important distinction in interpreting Lrrk2 function

Lrrk2 Pleomorphic Pathology

Lrrk2 has been dubbed the “Rosetta stone” of parkinsonism pathology. Most autopsy-examined cases of Lrrk2 parkinsonism (~80%) show typical Lewy body disease that is consistent with a postmortem diagnosis of “definite” PD.47., 64., 71., 72. Some brains have only tau-positive neurofibrillary tangles reminiscent of argyrophilic grains disease,65., 73. some have multiple ubiquitin-immunoreactive cytoplasmic or nuclear neuronal inclusions, and some show only nigral degeneration and gliosis without

Lrrk2 Functional Neuroscience

In the slime mold Dictyostelium discoideum, LRK-1, the ancestral othologue of vertebrate LRRK1/LRRK2, encodes a homolog of GbpC, the main high-affinity cGMP-binding protein required for the normal phosphorylation and cytoskeletal assembly of myosin during chemotaxis.13., 80. In the nematode worm C. elegans, knockout of the orthologue LRK-1 suggests the kinase determines the polarized sorting of synaptic vesicle proteins to axons by excluding them from dendrite-specific transport machinery in

Parsimonious Molecular Model of Lrrk2 Activity

Lrrk2 is postulated to be a member of the RIP kinase family of proteins, which are essential sensors of cellular stress.19 These proteins integrate many different upstream signals to initiate a few specific responses, including cell survival and inflammatory-inducing or death-inducing programs that are mediated through the JNK, ERK, p38, and NF-κB signaling pathways. Changes in MAPK signaling are apparent in Lrrk2 parkinsonism and PD, and modulation of these pathways may have therapeutic

Future Research

Pleomorphic pathology suggests that the normal function, and pathogenic mutations, of Lrrk2 must be more intimately associated with successful aging of the basal ganglia than a direct cause of disease. Most proteins genetically implicated in parkinsonism, whether involved in signaling, in synaptic connectivity, as chaperones, in redox sensing, or in protein degradation, may be considered in the same context.76 PD is multifactorial disorder influenced by a combination of genetic, environmental,

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