TY - JOUR
AU - Schapira, Anthony H. V.
AB - Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease. It has an age-adjusted prevalence of approximately 150 of 100 000 and 2% at age 75 years. The early clinical features predominantly involve motor deficits that include asymmetric onset of resting tremor (usually upper limb), bradykinesia, and rigidity. These are, for the most part, the consequence of loss of dopaminergic neurons in the substantia nigra pars compacta. An important morphological hallmark of PD is the presence of Lewy bodies in a proportion of surviving neurons. Study of the etiology and pathogenesis of P D has provided invaluable insights into the molecular mechanisms that may underlie neuronal dysfunction and degeneration in this disease. Perhaps the most important of these is the identification of 6 different genes implicated in the cause of PD: α-synuclein, parkin, UCHL1, DJ1, PINK1, and LRRK2. With the exception of LRRK2, all are relatively rare, and furthermore, there remains some debate regarding the authenticity of the UCHL1 mutation. Mutations of LRRK2, however, are the most common causes of PD identified to date. An understanding of the normal function(s) of the LRRK2 protein and the molecular consequences of mutations in this gene are of fundamental importance to PD research. Characterization of the genotype-phenotype (clinical and pathological) correlates is essential to our understanding of not just the contribution of this protein to PD, but how other gene mutations may also induce PD. Lrrk2 protein The LRRK2 gene (Figure) comprises at least 51 exons and is predicted to encode a 2527–amino acid (approximately 275-kDa) protein. The gene has multiple transcription initiation sites.1 Northern blot analysis demonstrates a possible 9–kilobase pair messenger RNA transcript that appears to be ubiquitously expressed.2 In human substantia nigra at least, there was no evidence of alternative splicing, although there was evidence of a cryptic splice site in a minority of messenger RNA species that might produce an isoform with the exclusion of 6 amino acids near the WD40 domain.1 Northern blot analyses have shown rich expression in dopamine-innervated areas but little or no expression in dopamine neurons. Figure. View LargeDownload The LRRK2 gene comprises 7581 base pairs and 51 exons and is predicted to encode a protein of approximately 275 kDa. LRRK2 antibodies have confirmed a wide distribution of the protein throughout the brain and peripheral tissues.3 LRRK2 is a predominantly cytoplasmic membrane–associated rather than a membrane-bound protein and is present in microsomal and outer mitochondrial membrane fractions, approximately 10% of the protein being associated with the latter.1,4,5 LRRK2 belongs to the Roco protein family, part of the RAS/GTPase superfamily, and contains several domains: Roc domain (Ras in complex proteins), COR domain (C terminal of Roc), N terminal leucine-rich repeats and a protein kinase domain (mitogen-activated protein kinase kinase kinase [MAPKKK]), and a C terminal WD40 domain. This complex suggests multiple activities that might include intramolecular signal transduction and function as a scaffolding protein. Full-length LRRK2 interacts with itself undergoing dimerization, although the kinase domain does not mediatethis interaction. The kinase domain appears to be cytosolic. The kinase activity of LRRK2 is considered important in the pathogenesis of mutations that result in PD (see later). Human LRRK1 is a closely related paralogue of LRRK2 with an identical domain structure. Studies have confirmed that LRRK1 is a functional protein kinase and a guanine nucleotide diphosphate/guanine nucleotide triphosphate–binding protein.6 Binding of guanine nucleotide triphosphate to the Roc domain of LRRK1 stimulates kinase activity, and mutations corresponding to those found in LRRK2 cause loss of kinase activity. An interesting and unexpected finding was the interaction of LRRK2 with parkin.4 The RING2 domain of parkin and the COR domain of LRRK2 are required for this interaction. Although a small number of LRRK2-overexpressing cells showed punctate areas suggestive of aggregates, cotransfection with parkin resulted in a significant increase in ubiquitinated aggregates. LRRK2 was not ubiquitinated by parkin, an E3 ubiquitin ligase, but LRRK2 did induce a 25-fold increase in parkin autoubiquitination and a 3-fold increase in parkin protein. There was no evidence that α-synuclein, DJ1, or tau interacted with LRRK2 and no evidence that LRRK2 phosphorylated parkin or α-synuclein.1 LRRK2 MUTATIONS Mutations of the LRRK2 gene causing PD have now been described in all main protein domains. There is no distinction at present between the site of a mutation and any specific clinical phenotype. Wild-type LRRK2 protein undergoes autophosphorylation; the kinase domain mutation I2020T significantly increased this activity by approximately 40%5 and a similar effect was seen with the G2019S and, less so, with the R1441C mutations.1 LRRK2 autophosphorylation may represent a mechanism to regulate the parent protein. Mutations of the Roc, COR, or kinase domains do not appear to modify intracellular distribution in overexpression lines. LRRK2 mutations are autosomal dominant with variable penetrance (see later). The dominant inheritance may be a consequence of a “gain of function” or a loss of function with haploinsufficiency. An increase in kinase activity as a result of the G2019S and I2020T mutations supports a gain-of-function model. These 2 mutations occur at an important region of the kinase catalytic site that regulates substrate access and may actually increase substrate interaction.7 Mutations at a similar regulatory site in BRAF kinase increase kinase activity and are associated with malignant melanoma formation.8 Overexpression of either of 3 LRRK2 mutants (G2019S, R1441C, and Y1699C), but not wild-type, reduced cell viability via apoptosis in SHSY5Y cells and degeneration in transfected mouse primary cortical neurons.4 LRRK2 EPIDEMIOLOGICAL FEATURES To date, LRRK2 mutations have been found in 5% to 8% of individuals with a first-degree relative with PD and in 0.4% to 1.6% of patients with apparently sporadic PD.9-18 Several different LRRK2 mutations have been reported to date and no doubt many others will be described. The G2019S mutation in the kinase domain is the most common and alone accounts for the majority of cases referenced earlier. This mutation probably has a common founder within Europe and North Africa and may have arisen in the 13th century.19 Although a common cause of PD in European and North American populations, it appears to be even more common in North African populations, where the frequency among families with PD was 41%.20 This study also identified a patient from Algeria who was homozygous for the G2019S mutation, with onset of typical PD at age 56 years, indicating that there is no gene-dose effect. The penetrance of this mutation is age dependent, increasing from 17% at age 50 years to 85% at age 70 years,14 a striking similarity to sporadic PD. In the French–North African study, penetrance was 33% at age 55 years and 100% at 76 years and older.20 Individuals with LRRK2 mutations and no or minimal neurological features in the eighth or ninth decade have been described.21 Two studies have addressed the issue of whether common genetic variation within LRRK2 influences the risk for sporadic, idiopathic PD. Analysis of patients with PD in Germany found no association,22 but a haplotype in the Chinese population significantly increased risk (odds ratio, 5.5 [95% confidence interval, 2.1-14.0]) when present in 2 copies.23 CLINICAL FEATURES OF LRRK2 MUTATIONS In this issue of the ARCHIVES, Papapetropoulos et al24 report that 4 of 130 pathologically confirmed PD brains and 1 of 85 controls with no evidence of neurodegeneration had the G2019S mutation.24 No samples had either the I2020T or I2012T mutations. Age at onset of PD varied from 41 years to 79 years; in 3 of the patients, clinical features were fairly typical of PD but with the oldest case exhibiting early falls, kinetic tremor, and a relative insensitivity to levodopa. Only 1 of the 4 patients had a family history. The pathological features of all the PD cases were considered typical. The 1 control brain with the G2019S mutation was from a 68-year-old man with no symptoms of PD who died of a myocardial infarction. This study again confirms the importance of the G2019S mutation as a cause of PD. Importantly, 4 of 130 brains with pathological features typical of PD had this mutation, emphasizing its relationship to Lewy body–positive nigral degeneration, although additional pathological features may be seen in some brains. The presence of the mutation in a control brain from an individual who died at age 68 years could in part reflect death before onset of PD, although one might have expected some early pathological features if he were in the presymptomatic phase. Alternatively, this case may be another example of the limited penetrance of LRRK2 mutations in some individuals. Clinical, imaging, and pathological review of 1 of the large UK pedigrees with a LRRK2 mutation (Y1699C) again provides many parallels with sporadic PD.25 Mean age at onset was 57 years and a frequent feature was the onset of symptoms in the lower limb with tremor or dystonia. Progression was relatively slow, response to levodopa was good, motor complications were mild or significantly delayed, and cognition was normal. Fluorodopa F 18 positron emission tomography results were typical of those seen in sporadic PD. One case came to autopsy and showed severe loss of dopaminergic neurons in the dorsal and ventral tiers of the nigra with Lewy body formation in the nigra, olfactory bulb, and cortex (corresponding to brainstem-predominant Lewy body disease). Neurofibrillary tangles were present in the hippocampus, corresponding to Braak and Braak stage II. Fifteen members of 2 LRRK2 kindreds were imaged using a variety of scanning techniques.26 One (family A) had the Y1699C mutation in the COR domain and the other (family D), the R1441C mutation in the Roc domain. There was no difference in the clinical or imaging features between these. For the most part, affected individuals had typical levodopa-responsive PD, although some members of family A also had dystonia, dementia, epilepsy, and amyotrophy. Pathological features included nigral neuronal loss and gliosis in all cases examined, with some pleomorphic changes in others. Fluorodopa F 18 positron emission tomography showed changes typical of sporadic PD with asymmetric rostrocaudal loss predominantly in the putamen. Likewise, imaging for the vesicular monoamine transporter with α-dihydrotetrabenazine labeled with radioactive carbon (11C) and with d-threo-methylphenidate labeled with radioactive carbon (11C) for the dopamine transporter was similar to sporadic PD. Raclopride binding in 2 patients was normal. Interestingly, 2 asymptomatic carriers had reduced putaminal dopamine transporter binding but normal fluorodopa F 18 positron emission tomography results. This pattern was also seen on follow-up scans of 2 additional asymptomatic carriers who were 10 years younger than the average age at onset in their respective families. PATHOLOGICAL FEATURES OF LRRK2 MUTATIONS A study investigated brains from 46 patients with PD and 34 patients with dementia with Lewy bodies and found the G2019S mutation in 3.3 One early-onset case (aged 47 years) had typical clinical and pathological features of PD. An older-onset patient (aged 76 years) again had reasonably typical PD with pathological features of Alzheimer disease or the Lewy body variant of PD. The third patient with some atypical clinical features with age at onset of 59 years showed extensive pigmented neuronal loss in the substantia nigra and locus ceruleus but no Lewy bodies or α-synuclein inclusions. LRRK2 protein was not identified in α-synuclein or tau inclusions in any of these 3 but was present in dystrophic neuritis of the third patient. In other cases of the G2019S mutation, pathological features have been typical of PD,24 although some have also shown neocortical senile plaques and neurofibrillary tangles.10 The Sagamihara kindred in whom a LRRK2 gene mutation was first associated, but not identified, was subsequently shown to have the I2020T mutation.27 The pathological features in this family are those of pure nigral degeneration without Lewy bodies or α-synuclein pathological characteristics. The Y1699C mutation has been associated with parkinsonism, dementia, and amyotrophy and ubiquitin-positive cytoplasmic and nuclear inclusions.28 One patient with the R1441C mutation had tau pathological features suggestive of progressive supranuclear palsy, while 2 had more typical PD pathological characteristics.29 Neither the R1441C nor G2019S LRRK2 mutations were identified in 242 cases of pathologically confirmed progressive supranuclear palsy.30 No LRRK2 mutations were identified in 242 Norwegian patients with dementia, most of whom had Alzheimer disease.31 Conclusions The discovery that LRRK2 mutations are a common cause of PD is of immense importance for several reasons. The G2019S mutation is a common cause of PD; it is not yet known whether other LRRK2 mutations will account for a significant proportion of remaining patients. Identifying the mechanisms by which such a large, ubiquitously expressed, multifunctional protein induces nigral neuronal cell death will no doubt provide invaluable insights into the causes of sporadic, “idiopathic” PD. Based on lessons learned from other PD mutations (eg, parkin, PINK1, and DJ1), mitochondrial dysfunction, oxidative stress, and proteasomal abnormalities are good places to begin the search. The pleomorphic pathological features found in some cases of the G2019S mutation may also provide insight into pathogenetic processes involving other neurodegenerations, including tau disorders. The similarity in the clinical features between LRRK2 and sporadic forms of PD is remarkable. However, the variable penetrance of, for instance, the G2019S mutation raises important questions regarding interaction with other genetic or environmental factors. Clues to these may come from the effects of LRRK2 mutations on the sensitivity of dopaminergic neurons to established toxins relevant to PD. While the asymmetry in the imaging of the patients with LRRK2 mutations is typical of that seen in PD, it is intriguing to consider how this may have arisen given the presumably symmetrical expression of the gene within the brain. It would seem premature to consider testing or genetic counseling for patients with PD of LRRK2 families outside the research context. Similarly, testing patients with sporadic PD for the G2019S mutation will not at this stage provide clinically useful information. The substantial variation in penetrance discussed earlier prevents the provision of any appropriate advice on prognosis for individual patients. If increased kinase activity in LRRK2 plays an important role in pathogenesis, this may provide a useful target for therapeutic intervention. Unless a similar process is relevant to other cases of PD, however, benefits might be confined to those with, for instance, the G2019S mutation. Nevertheless, phosphorylation plays an important role in α-synuclein pathogenesis and kinases other than LRRK2 may in time prove suitable candidates for drug intervention. Otherwise the kinase-enhancing mutations of LRRK2 might represent an early example of targeted pharmacogenomics. Back to top Article Information Correspondence: Prof Schapira, University Department of Clinical Neurosciences, Royal Free and University College Medical School, Rowland Hill St, London NW3 2PF, United Kingdom (a.schapira@medsch.ucl.ac.uk). References 1. West ABMoore DJBiskup S et al. Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci U S A 2005;10216842- 16847PubMedGoogle ScholarCrossref 2. Paisan-Ruiz CJain SEvans EW et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron 2004;44595- 600PubMedGoogle ScholarCrossref 3. Giasson BICovy JPBonini NM et al. Biochemical and pathological characterization of Lrrk2. Ann Neurol 2006;59315- 322PubMedGoogle ScholarCrossref 4. Smith WWPei ZJiang H et al. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A 2005;10218676- 18681PubMedGoogle ScholarCrossref 5. Gloeckner CJKinkl NSchumacher A et al. The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity. Hum Mol Genet 2006;15223- 232PubMedGoogle ScholarCrossref 6. Korr DToschi LDonner PPohlenz HDKreft BWeiss B LRRK1 protein kinase activity is stimulated upon binding of GTP to its Roc domain. Cell Signal 2006;18910- 920PubMedGoogle ScholarCrossref 7. Nolen BTaylor SGhosh G Regulation of protein kinases; controlling activity through activation segment conformation. Mol Cell 2004;15661- 675PubMedGoogle ScholarCrossref 8. Davies HBignell GRCox C et al. Mutations of the BRAF gene in human cancer. Nature 2002;417949- 954PubMedGoogle ScholarCrossref 9. Farrer MStone JMata IF et al. LRRK2 mutations in Parkinson disease. Neurology 2005;65738- 740PubMedGoogle ScholarCrossref 10. Gilks WPAbou-Sleiman PMGandhi S et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 2005;365415- 416PubMedGoogle Scholar 11. Zabetian CPSamii AMosley AD et al. A clinic-based study of the LRRK2 gene in Parkinson disease yields new mutations. Neurology 2005;65741- 744PubMedGoogle ScholarCrossref 12. Deng HLe WGuo YHunter CBXie WJankovic J Genetic and clinical identification of Parkinson's disease patients with LRRK2 G2019S mutation. Ann Neurol 2005;57933- 934PubMedGoogle ScholarCrossref 13. Di Fonzo ARohe CFFerreira J et al. A frequent LRRK2 gene mutation associated with autosomal dominant Parkinson's disease. Lancet 2005;365412- 415PubMedGoogle ScholarCrossref 14. Kachergus JMata IFHulihan M et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet 2005;76672- 680PubMedGoogle ScholarCrossref 15. Hernandez DPaisan RCCrawley A et al. The dardarin G 2019 S mutation is a common cause of Parkinson's disease but not other neurodegenerative diseases. Neurosci Lett 2005;389137- 139PubMedGoogle ScholarCrossref 16. Nichols WCPankratz NHernandez D et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet 2005;365410- 412PubMedGoogle Scholar 17. Aasly JOToft MFernandez-Mata I et al. Clinical features of LRRK2-associated Parkinson's disease in central Norway. Ann Neurol 2005;57762- 765PubMedGoogle ScholarCrossref 18. Di Fonzo ATassorelli CDe Mari M et al. Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease. Eur J Hum Genet 2006;14322- 331PubMedGoogle ScholarCrossref 19. Lesage SLeutenegger ALIbanez P et al. LRRK2 haplotype analyses in European and North African families with Parkinson disease: a common founder for the G2019S mutation dating from the 13th century. Am J Hum Genet 2005;77330- 332PubMedGoogle ScholarCrossref 20. Lesage SIbanez PLohmann E et al. G2019S LRRK2 mutation in French and North African families with Parkinson's disease. Ann Neurol 2005;58784- 787PubMedGoogle ScholarCrossref 21. Kay DMKramer PHiggins DZabetian CPPayami H Escaping Parkinson's disease: a neurologically healthy octogenarian with the LRRK2 G2019S mutation. Mov Disord 2005;201077- 1078PubMedGoogle ScholarCrossref 22. Biskup SMueller JCSharma M et al. Common variants of LRRK2 are not associated with sporadic Parkinson's disease. Ann Neurol 2005;58905- 908PubMedGoogle ScholarCrossref 23. Skipper LLi YBonnard C et al. Comprehensive evaluation of common genetic variation within LRRK2 reveals evidence for association with sporadic Parkinson's disease. Hum Mol Genet 2005;143549- 3556PubMedGoogle ScholarCrossref 24. Papapetropoulos SSinger CRoss OA et al. Clinical heterogeneity of the LRRK2 G2019S mutation. Arch Neurol 2006;631242- 1246Google ScholarCrossref 25. Khan NLJain SLynch JM et al. Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data. Brain 2005;1282786- 2796PubMedGoogle ScholarCrossref 26. Adams JRvan Netten HSchulzer M et al. PET in LRRK2 mutations: comparison to sporadic Parkinson's disease and evidence for presymptomatic compensation. Brain 2005;1282777- 2785PubMedGoogle ScholarCrossref 27. Funayama MHasegawa KOhta E et al. An LRRK2 mutation as a cause for the parkinsonism in the original PARK8 family. Ann Neurol 2005;57918- 921PubMedGoogle ScholarCrossref 28. Zimprich ABiskup SLeitner P et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44601- 607PubMedGoogle ScholarCrossref 29. Wszolek ZKPfeiffer RFTsuboi Y et al. Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 2004;621619- 1622PubMedGoogle ScholarCrossref 30. Ross OAWhittle AJCobb SA et al. Lrrk2 R1441 substitution and progressive supranuclear palsy. Neuropathol Appl Neurobiol 2006;3223- 25PubMedGoogle ScholarCrossref 31. Toft MSando SBMelquist S et al. LRRK2 mutations are not common in Alzheimer's disease. Mech Ageing Dev 2005;1261201- 1205PubMedGoogle ScholarCrossref
TI - The Importance of LRRK2 Mutations in Parkinson Disease
JF - Archives of Neurology
DO - 10.1001/archneur.63.9.1225
DA - 2006-09-01
UR - https://www.deepdyve.com/lp/american-medical-association/the-importance-of-lrrk2-mutations-in-parkinson-disease-blxdrvj1ve
SP - 1225
EP - 1228
VL - 63
IS - 9
DP - DeepDyve
ER -