Note: Sergey Brin has the LRRK2 gene mutation which is associated with 50% chance of his getting early-onset Parkinson’s Disease in the next 10 years
Table of contents
- LRRK2 and neuroinflammation: partners in crime in Parkinson's disease? – March 2014 PDF attached
- THE KINASE LRRK2, MUTATED IN PARKINSONS DISEASE, IS REQUIRED FOR VITAMIN D3 AND PHOSPHATE METABOLISM = June 2013
- Genetic insights into sporadic Parkinson's disease pathogenesis. Dec 2013 PDF attached
- Review of Early onset PD and gene mutations – Oct 2012
- What genetics tells us about the causes and mechanisms of Parkinson's disease. – Oct 2011 PDF attached
- What genetics tells us about the causes decreased in rats with curcumin (LRRK2 gene) – Jan 2010
- History of Genetics and PD: Medscape 2012
- Parkinson’s Disease relationship to Vitamin D
- LRRK2 at GeneCards - extensive details
J Neuroinflammation. 2014 Mar 21;11:52. doi: 10.1186/1742-2094-11-52.
Russo I 1, Bubacco L, Greggio E.
Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35121 Pad ova, Italy. isabella.russo at unipd.it.
It is now well established that chronic inflammation is a prominent feature of several neurodegenerative disorders including Parkinson's disease (PD). Growing evidence indicates that neuroinflammation can contribute greatly to dopaminergic neuron degeneration and progression of the disease. Recent literature highlights that leucine-rich repeat kinase 2 (LRRK2), a kinase mutated in both autosomal-dominantly inherited and sporadic PD cases, modulates inflammation in response to different pathological stimuli. In this review, we outline the state of the art of LRRK2 functions in microglia cells and in neuroinflammation. Furthermore, we discuss the potential role of LRRK2 in cytoskeleton remodeling and vesicle trafficking in microglia cells under physiological and pathological conditions. We also hypothesize that LRRK2 mutations might sensitize microglia cells toward a pro-inflammatory state, which in turn results in exacerbated inflammation with consequent neurodegeneration.
THE KINASE LRRK2, MUTATED IN PARKINSONS DISEASE, IS REQUIRED FOR VITAMIN D3 AND PHOSPHATE METABOLISM = June 2013
Acta Physiologica 2013; Volume 207, Supplement 694, 92nd Annual Meeting of the German Physiological Society, 02/03/2013-05/03/2013, Heidelberg, Germany
Abstract number: O15
Mühlemann 1 R. , Minder 1 N., Bettoni 1 C., Ruminska 1 J., Daryadel 1 A., Schnitzbauer 1 U., Kumar 1 M., Mohebbi 1 N., Biber 1 J., Hernando 1 N., Rovelli 2 G., Shimshek 2 D., van der Putten 2 H., Wagner 1 *C.
1 University of Zurich, Institute of Physiology, Zurich, Switzerland
2 Novartis Institutes for Biomedical Research, Basel, Switzerland
Mutations in the Leucine Rich Repeat Kinase (LRRK2, Park8) underlie about 5 % of familial and 1-2 % of sporadic cases of Parkinson disease (PD). LRRK2 is almost ubiquitously expressed with particularly high levels in kidney, lung, and brain. The role of LRRK2, its up- and downstream regulators and targets are unknown. Here we show in mice either lacking Lrrk2 or expressing the G2019S mutant (the most common mutation in PD patients) and in rats deficient for LRRK2 that phosphate metabolism is highly disturbed. The levels of PTH, FGF23, and 1,25OH2-vitamin D3 are altered in all three animal models. Renal phosphate excretion is increased in animals lacking Lrrk2 and decreased in G2019S mutants. Expression of the vitamin D receptor and the vitamin D activating and inactivating enzymes Cyp27b1 and Cyp24a1, as well as of klotho (coligand for FGF23) are altered in most organs expressing LRRK2. Changes in dietary phosphate intake in Lrrk2 WT and KO mice alter phosphate and vitamin D target genes in a LRRK2 dependent manner and application of vitamin D3 to wildtype mice increases LRRK2 expression. In vitro, inhibition of LRRK2 alters expression of Cyp24a1 and the intestinal phosphate transporter NaPiIIb. Our data suggest that LRRK2 plays a central role in regulating phosphate metabolism and hormones involved in its control.
Curr Genomics. 2013 Dec;14(8):486-501. doi: 10.2174/1389202914666131210195808.
Chai C1, Lim KL2.
1Duke-NUS Graduate Medical School, Singapore.
2Duke-NUS Graduate Medical School, Singapore ; Department of Physiology, National University of Singapore, Singapore ; Neurodegeneration Research Laboratory, National Neuroscience Institute, Singapore.
Intensive research over the last 15 years has led to the identification of several autosomal recessive and dominant genes that cause familial Parkinson's disease (PD). Importantly, the functional characterization of these genes has shed considerable insights into the molecular mechanisms underlying the etiology and pathogenesis of PD. Collectively; these studies implicate aberrant protein and mitochondrial homeostasis as key contributors to the development of PD, with oxidative stress likely acting as an important nexus between the two pathogenic events. Interestingly, recent genome-wide association studies (GWAS) have revealed variations in at least two of the identified familial PD genes (i.e. α-synuclein and LRRK2) as significant risk factors for the development of sporadic PD. At the same time, the studies also uncovered variability in novel alleles that is associated with increased risk for the disease. Additionally, in-silico meta-analyses of GWAS data have allowed major steps into the investigation of the roles of gene-gene and gene-environment interactions in sporadic PD. The emergent picture from the progress made thus far is that the etiology of sporadic PD is multi-factorial and presumably involves a complex interplay between a multitude of gene networks and the environment. Nonetheless, the biochemical pathways underlying familial and sporadic forms of PD are likely to be shared.
_Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease.
Mov Disord. 2012 Oct;27(12):1522-9. doi: 10.1002/mds.25132. Epub 2012 Sep 6.
Kilarski LL1, Pearson JP, Newsway V, Majounie E, Knipe MD, Misbahuddin A, Chinnery PF, Burn DJ, Clarke CE, Marion MH, Lewthwaite AJ, Nicholl DJ, Wood NW, Morrison KE, Williams-Gray CH, Evans JR, Sawcer SJ, Barker RA, Wickremaratchi MM, Ben-Shlomo Y, Williams NM, Morris HR.
Approximately 3.6% of patients with Parkinson's disease develop symptoms before age 45. Early-onset Parkinson's disease (EOPD) patients have a higher familial recurrence risk than late-onset patients, and 3 main recessive EOPD genes have been described. We aimed to establish the prevalence of mutations in these genes in a UK cohort and in previous studies. We screened 136 EOPD probands from a high-ascertainment regional and community-based prevalence study for pathogenic mutations in PARK2 (parkin), PINK1, PARK7 (DJ-1), and exon 41 of LRRK2. We also carried out a systematic review, calculating the proportion of cases with pathogenic mutations in previously reported studies. We identified 5 patients with pathogenic PARK2, 1 patient with PINK1, and 1 with LRRK2 mutations. The rate of mutations overall was 5.1%. Mutations were more common in patients with age at onset (AAO) < 40 (9.5%), an affected first-degree relative (6.9%), an affected sibling (28.6%), or parental consanguinity (50%). In our study EOPD mutation carriers were more likely to present with rigidity and dystonia, and 6 of 7 mutation carriers had lower limb symptoms at onset. Our systematic review included information from >5800 unique cases. Overall, the weighted mean proportion of cases with PARK2 (parkin), PINK1, and PARK7 (DJ-1) mutations was 8.6%, 3.7%, and 0.4%, respectively. PINK1 mutations were more common in Asian subjects. The overall frequency of mutations in known EOPD genes was lower than previously estimated. Our study shows an increased likelihood of mutations in patients with lower AAO, family history, or parental consanguinity.
Copyright © 2012 Movement Disorder Society.
What genetics tells us about the causes and mechanisms of Parkinson's disease. – Oct 2011 PDF attached
Physiol Rev. 2011 Oct;91(4):1161-218. doi: 10.1152/physrev.00022.2010.
Corti O1, Lesage S, Brice A.
1Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière; Institut National de la Santé et de la Recherche Médicale U.975, Paris, France.
Parkinson's disease (PD) is a common motor disorder of mysterious etiology. It is due to the progressive degeneration of the dopaminergic neurons of the substantia nigra and is accompanied by the appearance of intraneuronal inclusions enriched in α-synuclein, the Lewy bodies. It is becoming increasingly clear that genetic factors contribute to its complex pathogenesis. Over the past decade, the genetic basis of rare PD forms with Mendelian inheritance, representing no more than 10% of the cases, has been investigated. More than 16 loci and 11 associated genes have been identified so far; genome-wide association studies have provided convincing evidence that polymorphic variants in these genes contribute to sporadic PD. The knowledge acquired of the functions of their protein products has revealed pathways of neurodegeneration that may be shared between inherited and sporadic PD. An impressive set of data in different model systems strongly suggest that mitochondrial dysfunction plays a central role in clinically similar, early-onset autosomal recessive PD forms caused by parkin and PINK1, and possibly DJ-1 gene mutations.
In contrast, α-synuclein accumulation in Lewy bodies defines a spectrum of disorders ranging from typical late-onset PD to PD dementia and including sporadic and autosomal dominant PD forms due to mutations in SCNA and LRRK2.
However, the pathological role of Lewy bodies remains uncertain, as they may or may not be present in PD forms with one and the same LRRK2 mutation. Impairment of autophagy-based protein/organelle degradation pathways is emerging as a possible unifying but still fragile pathogenic scenario in PD. Strengthening these discoveries and finding other convergence points by identifying new genes responsible for Mendelian forms of PD and exploring their functions and relationships are the main challenges of the next decade. It is also the way to follow to open new promising avenues of neuroprotective treatment for this devastating disorder.
Curcumin exposure induces expression of the Parkinson's disease-associated leucine-rich repeat kinase 2 (LRRK2) in rat mesencephalic cells.
Neurosci Lett. 2010 Jan 4;468(2):120-4. Epub 2009 Oct 30
Ortiz-Ortiz MA, Moran JM, Ruiz-Mesa LM, Niso-Santano M, Bravo-SanPedro
JM, Gomez-Sanchez R, Gonzalez-Polo RA, Fuentes JM.
Centro de Investigacion Biomedica en Red de Enfermedades
Neurodegenerativas, Departamento de Bioquimica y Biologia Molecular y
Genetica, EU Enfermeria y TO, Universidad de Extremadura, Avda
Universidad s/n, 10071 Caceres, Spain.
Turmeric (curry powder), an essential ingredient of culinary preparations of Southeast Asia, contains a major polyphenolic compound
known as curcumin or diferuloylmethane. Curcumin is a widely studied phytochemical with a variety of biological activities. In addition to
its anti-inflammatory and antimicrobial/antiviral properties, curcumin is considered as a cancer chemopreventive agent as well as a modulator
of gene expression and a potent antioxidant. Since oxidative stress has been implicated in the degeneration of dopaminergic neurons in the
substantia nigra in Parkinson's disease (PD), curcumin has been proposed to have potential therapeutic value for the treatment of
neurodegenerative diseases such as PD. Following age, a family history of PD is the most commonly reported risk factor, suggesting a genetic
component of the disease in a subgroup of patients. The LRRK2 gene has emerged as the gene most commonly associated with both familial and
sporadic PD. Here, we report that exposure of rat mesencephalic cells to curcumin induces the expression of LRRK2 mRNA and protein in a
time-dependent manner. The expression of other PD-related genes, such alpha-synuclein and parkin, was not affected by exposure to curcumin,
and PTEN-induced putative kinase 1 (PINK1) was not expressed in rat mesencephalic cells. As LRRK2 overexpression is strongly associated with [
the pathological inclusions found in several neurodegenerative disorders, further studies are needed to evaluate the effects of
curcumin as a therapeutic agent for neurodegenerative diseases.
A link between Parkinson disease (PD) and mutations in the leucine-rich repeat kinase-2 gene LRRK2 was first discovered in the early 21st century . In 2002, Funayama and colleagues reported a large Japanese kindred with an autosomal-dominant form of PD that was linked to a novel genetic risk locus on chromosome 12. This locus, designated as PARK8, was subsequently associated with familial PD in Caucasian families. In 2004, 2 groups simultaneously identified the genetic cause underlying PARK8-associated PD when they described mutations in LRRK2.[2, 3]
Since this discovery, a large number of novel LRRK2 mutations have been described as putative causes of PD. While it is likely that many of these are truly pathogenic mutations, proof of pathogenicity is difficult, and only 5 LRRK2 mutations (G2019S, R1441C, R1441G, I2020T, and Y1699C) are unequivocally linked to disease based on disease segregation in large families and functional studies.[4, 5, 6, 7]
Comprehensive mutation screening has shown that frequencies of LRRK2 mutations vary significantly across different ethnic groups. A good example is the G2019S mutation, the most common LRRK2 mutation in Caucasian populations. Within outbred Caucasian populations, this single change is believed to underlie approximately 5% of PD cases with a family history of PD and approximately 2% of apparently sporadic PD cases,[8, 9] thus accounting for approximately half of all LRRK2 mutations in these populations.
In Ashkenazi Jewish communities, about 40% of familial and 13% of sporadic cases carry this mutation, and, in North African Berber Arabs, the frequency is even higher; specifically, 39% of familial cases and 40% of sporadic cases. In contrast, in Asian populations, this mutation is only rarely detected.[10, 11, 12, 13, 14] Of note, genetic data point toward a single founder for the vast majority of the G2019S PD cases.
Genetic risk modifiers
In addition to the above-mentioned disease-causing mutations characterized by segregation with disease in large families, there are 2 lines of evidence that support the idea that the LRRK2 locus also contains risk-modifying variants. The first line of evidence comes from studies within Asian populations showing that 2 protein-coding variants, G2385R and R1628P, increase the risk for PD approximately 2-fold; these mutations are present at a frequency of approximately 6% in cases, and approximately half that in controls.[16, 17]
The second line of evidence comes from genome-wide association studies that implicate noncoding variants close to LRRK2 with altered risk for PD and that suggest this risk may be mediated by altering the expression and/or splicing of LRRK2.
The penetrance of LRRK2 mutations has been a topic of intense study and debate.
The most parsimonious models employ age-based penetrance estimates, which suggest that the G2019S mutation has a penetrance of
- 28% at age 59 years,
- 51% at age 69 years, and
- 74% at age 79 years.
For the R1441G change, a mutation with high prevalence in the Basque population, penetrance estimates are
- 13% at age 65 years, increasing to
- 83% at age 80 years.[19, 20]
Penetrance estimates have not been established for other LRRK2 mutations.
Clinically, the presentation of typical LRRK2 -related PD is indistinguishable from idiopathic PD with late-onset, levodopa-responsive parkinsonism.
In some cases, however, atypical features have been observed, including the following [2, 15, 21, 22] :
Early disease onset
Dystonia of lower extremities
Variability also exists with respect to the neuropathology, ranging from Lewy body PD to nigral degeneration without distinctive histopathology, or tau-positive neurofibrillary tangle pathology.[2, 23]
Clinical Implications and Genetic Testing
To date, knowledge about LRRK2 -mutation status does not alter therapeutic management, since targeted, neuroprotective therapies are still at an experimental stage. Clinical implications are, therefore, limited to the identification of mutation carriers for research studies. Thus, routine genetic testing for LRRK2 mutations remains a controversial topic; this is particularly true when testing of asymptomatic relatives of PD patients is considered.
Within the context of a research study, information on the ethnic background of a proband allows testing for mutations that are most prevalent in that ethnic population, thereby avoiding excessive and costly screening. In individuals of Caucasian, Ashkenazi Jewish, or North African Berber ancestry, testing for the G2019S mutation would be recommended, while patients of Spanish or Hispanic descent should also be evaluated for R1441G mutations. Given the limited knowledge on clinical consequences of the common risk-modifying variants G2385R and R1628P, genetic screening for these mutations should not be encouraged.
PD associated with LRRK2 mutations is an autosomal-dominant disease. It therefore follows that each child of an LRRK2 mutation carrier has a 50% chance of inheriting the mutation. However, due to incomplete penetrance, only a fraction of these individuals will develop disease, and age is the main risk factor influencing disease penetrance.
Current therapy for PD focuses on drugs that manage the symptoms but do not affect the disease progression. Research is being conducted that involves inhibitors of kinases (enzymes that regulate cellular signaling) and how they may affect the neurologic pathways associated with PD. Unfortunately, at this time, the repeated failure of neuroprotective drugs in animal models suggests that there are likely multiple processes involved. A coalescing molecular pathway for the disease still remains elusive.[24, 25, 26]
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- Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. Nov 18 2004;44(4):601-7. [Medline].
- Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease. Neuron. Nov 18 2004;44(4):595-600. [Medline].
- Greggio E, Cookson MR. Leucine-rich repeat kinase 2 mutations and Parkinson's disease: three questions. ASN Neuro. Apr 14 2009;1(1):[Medline]. [Full Text].
- Vancraenenbroeck R, Lobbestael E, Weeks SD, et al. Expression, purification and preliminary biochemical and structural characterization of the leucine rich repeat namesake domain of leucine rich repeat kinase 2. Biochim Biophys Acta. Jan 11 2012;1824(3):450-460. [Medline].
- Wang X, Yan MH, Fujioka H, et al. LRRK2 Regulates Mitochondrial Dynamics and Function through Direct Interaction with DLP1. Hum Mol Genet. Jan 6 2012;[Medline].
- Aasly JO, Shi M, Sossi V, et al. Cerebrospinal fluid amyloid ß and tau in LRRK2 mutation carriers. Neurology. Jan 3 2012;78(1):55-61. [Medline].
- Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, et al. A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet. Jan 29-Feb 4 2005;365(9457):415-6. [Medline].
- Nichols WC, Pankratz N, Hernandez D, Paisán-Ruíz C, Jain S, Halter CA, et al. Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease. Lancet. Jan 29-Feb 4 2005;365(9457):410-2. [Medline].
- Ozelius LJ, Senthil G, Saunders-Pullman R, Ohmann E, Deligtisch A, Tagliati M, et al. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med. Jan 26 2006;354(4):424-5. [Medline].
- Lesage S, Dürr A, Tazir M, Lohmann E, Leutenegger AL, Janin S, et al. LRRK2 G2019S as a cause of Parkinson's disease in North African Arabs. N Engl J Med. Jan 26 2006;354(4):422-3. [Medline].
- Bras JM, Guerreiro RJ, Ribeiro MH, Januario C, Morgadinho A, Oliveira CR, et al. G2019S dardarin substitution is a common cause of Parkinson's disease in a Portuguese cohort. Mov Disord. Dec 2005;20(12):1653-5. [Medline].
- Lu CS, Simons EJ, Wu-Chou YH, Fonzo AD, Chang HC, Chen RS, et al. The LRRK2 I2012T, G2019S, and I2020T mutations are rare in Taiwanese patients with sporadic Parkinson's disease. Parkinsonism Relat Disord. Dec 2005;11(8):521-2. [Medline].
- Tan EK, Shen H, Tan LC, Farrer M, Yew K, Chua E, et al. The G2019S LRRK2 mutation is uncommon in an Asian cohort of Parkinson's disease patients. Neurosci Lett. Aug 26 2005;384(3):327-9. [Medline].
- Goldwurm S, Di Fonzo A, Simons EJ, Rohé CF, Zini M, Canesi M, et al. The G6055A (G2019S) mutation in LRRK2 is frequent in both early and late onset Parkinson's disease and originates from a common ancestor. J Med Genet. Nov 2005;42(11):e65. [Medline]. [Full Text].
- Di Fonzo A, Wu-Chou YH, Lu CS, van Doeselaar M, Simons EJ, Rohé CF, et al. A common missense variant in the LRRK2 gene, Gly2385Arg, associated with Parkinson's disease risk in Taiwan. Neurogenetics. Jul 2006;7(3):133-8. [Medline].
- Ross OA, Wu YR, Lee MC, Funayama M, Chen ML, Soto AI, et al. Analysis of Lrrk2 R1628P as a risk factor for Parkinson's disease. Ann Neurol. Jul 2008;64(1):88-92. [Medline].
- Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, et al. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet. Feb 19 2011;377(9766):641-9. [Medline].
- Healy DG, Falchi M, O'Sullivan SS, Bonifati V, Durr A, Bressman S, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study. Lancet Neurol. Jul 2008;7(7):583-90. [Medline]. [Full Text].
- Ruiz-Martínez J, Gorostidi A, Ibañez B, Alzualde A, Otaegui D, Moreno F, et al. Penetrance in Parkinson's disease related to the LRRK2 R1441G mutation in the Basque country (Spain). Mov Disord. Oct 30 2010;25(14):2340-5. [Medline].
- Tomiyama H, Li Y, Funayama M, Hasegawa K, Yoshino H, Kubo S, et al. Clinicogenetic study of mutations in LRRK2 exon 41 in Parkinson's disease patients from 18 countries. Mov Disord. Aug 2006;21(8):1102-8. [Medline].
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