<i>LRRK2</i> G2019S Mutation: Prevalence and Clinical Features in Moroccans with Parkinson’s Disease

Bouhouche, Ahmed; Tibar, Houyam; Haj, Rafiqua Ben El; Bayad, Khalil El; Rachid, R.; Tazrout, S.; Skalli, A.; Bouslam, Naïma; Elouardi, Loubna; Benomar, Ali; Yahyaoui, M.; Regragui, W.

doi:10.1155/2017/2412486

Cited by 43 publications

(41 citation statements)

References 45 publications

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“…All patients agreed to participate and were recruited from October 2013 to June 2016 according to criteria described earlier [17]. Age at examination ranged from 35 to 86 years old and the mean age was 59 ± 11.4 years.…”

Section: Methodsmentioning

confidence: 99%

Evidence for prehistoric origins of the G2019S mutation in the North African Berber population

et al. 2017

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The most common cause of the monogenic form of Parkinson’s disease known so far is the G2019S mutation of the leucine-rich repeat kinase 2 (LRRK2) gene. Its frequency varies greatly among ethnic groups and geographic regions ranging from less than 0.1% in Asia to 40% in North Africa. This mutation has three distinct haplotypes; haplotype 1 being the oldest and most common. Recent studies have dated haplotype 1 of the G2019S mutation to about 4000 years ago, but it remains controversial whether the mutation has a Near-Eastern or Moroccan-Berber ancestral origin. To decipher this evolutionary history, we genotyped 10 microsatellite markers spanning a region of 11.27 Mb in a total of 57 unrelated Moroccan PD patients carrying the G2019S mutation for which the Berber or Arab origin was established over 3 generations based on spoken language. We estimated the age of the most recent common ancestor for the 36 Arab-speaking and the 15 Berber-speaking G2019S carriers using the likelihood-based method with a mutation rate of 10−4. Data analysis suggests that the shortest haplotype originated in a patient of Berber ethnicity. The common founder was estimated to have lived 159 generations ago (95% CI 116–224) for Arab patients, and 200 generations ago (95% CI 123–348) for Berber patients. Then, 29 native North African males carrying the mutation were assessed for specific uniparental markers by sequencing the Y-chromosome (E-M81, E-M78, and M-267) and mitochondrial DNA (mtDNA) hypervariable regions (HV1 and HV2) to examine paternal and maternal contributions, respectively. Results showed that the autochthonous genetic component reached 76% for mtDNA (Eurasian and north African haplogroups) and 59% for the Y-chromosome (E-M81 and E-M78), suggesting that the G2019S mutation may have arisen in an autochthonous DNA pool. Therefore, we conclude that LRRK2 G2019S mutation most likely originated in a Berber founder who lived at least 5000 years ago (95% CI 3075–8700).

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Section: Methodsmentioning

confidence: 99%

Evidence for prehistoric origins of the G2019S mutation in the North African Berber population

et al. 2017

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“…Kachergus and collaborators identified the G2019S mutation in 2005 (Kachergus et al., ), known as the most prevalent pathogenic mutation in LRRK2 that accounts for 5%–6% of autosomal‐dominant familial cases and 1%–2% of de novo generic PD cases in some Western populations (Gilks et al., ; Healy et al., ). The prevalence can be much higher depending on the population: a recent report suggested that as many as 70% of late‐onset PD patients seen at a neurology clinic in Morocco were positive for G2019S (Bouhouche et al., ). However, in far‐east Asian populations, the frequency of pathogenic LRRK2 mutations is extremely low (Tan et al., , ; Wu et al., ; Zabetian et al., ).…”

Section: Lrrk2 and The Kinase Hypothesis Of Lrrk2‐linked Pdmentioning

confidence: 99%

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

Cresto

Gardier

Gubinelli

et al. 2018

Eur J of Neuroscience

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Our understanding of the mechanisms underlying Parkinson's disease, the once archetypical nongenetic neurogenerative disorder, has dramatically increased with the identification of α‐synuclein and LRRK2 pathogenic mutations. While α‐synuclein protein composes the aggregates that can spread through much of the brain in disease, LRRK2 encodes a multidomain dual‐enzyme distinct from any other protein linked to neurodegeneration. In this review, we discuss emergent datasets from multiple model systems that suggest these unlikely partners do interact in important ways in disease, both within cells that express both LRRK2 and α‐synuclein as well as through more indirect pathways that might involve neuroinflammation. Although the link between LRRK2 and disease can be understood in part through LRRK2 kinase activity (phosphotransferase activity), α‐synuclein toxicity is multilayered and plausibly interacts with LRRK2 kinase activity in several ways. We discuss common protein interactors like 14‐3‐3s that may regulate α‐synuclein and LRRK2 in disease. Finally, we examine cellular pathways and outcomes common to both mutant α‐synuclein expression and LRRK2 activity and points of intersection. Understanding the interplay between these two unlikely partners in disease may provide new therapeutic avenues for PD.

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“…Leucine rich repeat kinase 2 (LRRK2) is a good target to improve our knowledge of these underlying processes as mutations within this protein are the most common cause for genetically driven forms of PD (5,6). LRRK2 is a complex and multifunctional protein consisting of seven closely interacting structural domains (7,8).…”

Section: Introductionmentioning

confidence: 99%

Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2

Schmidt

Weng²,

Aoto³

et al. 2020

Preprint

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In a multi-tiered approach, we explored how Parkinson's Disease-related mutations hijack the finely tuned activation process of Leucine-Rich Repeat Kinase 2 (LRRK2) using a construct containing the ROC, Cor, Kinase and WD40 domains (LRRK2RCKW). We hypothesized that the N-terminal domains shield the catalytic domains in an inactive state. PD mutations, type-I LRRK2 inhibitors, or physiological Rab GTPases can unleash the catalytic domains while the active kinase conformation, but not kinase activity, is essential for docking onto microtubules. Mapping solvent accessible regions of LRRK2RCKW employing hydrogen-deuterium exchange mass spectrometry (HDX-MS) revealed how inhibitor binding is sensed by the entire protein. Molecular Dynamics simulations of the kinase domain elucidated differences in conformational dynamics between wt and mutants of the DYGψ motif. While all domains contribute to regulating kinase activity and spatial distribution, the kinase domain, driven by the DYGψ motif, coordinates domain crosstalk and serves as an intrinsic hub for LRRK2 regulation.

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LRRK2 G2019S Mutation: Prevalence and Clinical Features in Moroccans with Parkinson’s Disease

Cited by 43 publications

References 45 publications

Evidence for prehistoric origins of the G2019S mutation in the North African Berber population

Evidence for prehistoric origins of the G2019S mutation in the North African Berber population

The unlikely partnership between LRRK2 and α‐synuclein in Parkinson's disease

Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2

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