Prevalence of ten LRRK2 variants in Parkinson's disease: A comprehensive review

Simpson, Christopher S.; Vinikoor-Imler, Lisa; Nassan, Feiby L.; Shirvan, Julia; Lally, Cathy; Dam, Tien; Maserejian, Nancy N.

doi:10.1016/j.parkreldis.2022.05.012

Cited by 36 publications

(30 citation statements)

References 173 publications

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“…Furthermore, other variations, such as G2385R, R1682P, and S1761R, have been discovered in PD patients and are considered to be pathogenic [ 82 , 83 , 84 ]. The recent study by Simpson et al reveals the prevalence of 10 LRRK2 mutations in PD [ 85 ]. There are multiple additional variations associated with PD risk, including A419V, N551K, R1325Q, R1398H, T1410M, R1628P, M1646T, S1647T, N2081D etc.…”

Section: Lrrk2 Mutationsmentioning

confidence: 99%

“…The substitution G2019S is the most often found mutation in PD patients, followed by the R1441G/H/C ROC domain mutation. The kinase domain mutation G2019S is not only reported in familial PD but also reported to contribute to 1–5% of sporadic PD cases [ 85 ]. It is noteworthy to mention that PD-associated mutations have been observed with different incidence and prevalence rates in different ethnic populations.…”

Section: Lrrk2 Mutationsmentioning

confidence: 99%

“…However, the mutation is rarely observed in Asian populations [ 91 , 92 , 93 ]. The second most kinase domain mutation associated with PD, I2020T, was observed in European and Asian populations but with lower frequencies [ 85 ]. The remaining kinase domain, I2012T, has only been reported in the Taiwanese population [ 94 ].…”

Section: Lrrk2 Mutationsmentioning

confidence: 99%

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Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, characterized by the specific loss of dopaminergic neurons in the midbrain. The pathophysiology of PD is likely caused by a variety of environmental and hereditary factors. Many single-gene mutations have been linked to this disease, but a significant number of studies indicate that mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are a potential therapeutic target for both sporadic and familial forms of PD. Consequently, the identification of potential LRRK2 inhibitors has been the focus of drug discovery. Various investigations have been conducted in academic and industrial organizations to investigate the mechanism of LRRK2 in PD and further develop its inhibitors. This review summarizes the role of LRRK2 in PD and its structural details, especially the kinase domain. Furthermore, we reviewed in vitro and in vivo findings of selected inhibitors reported to date against wild-type and mutant versions of the LRRK2 kinase domain as well as the current trends researchers are employing in the development of LRRK2 inhibitors.

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Section: Lrrk2 Mutationsmentioning

confidence: 99%

Section: Lrrk2 Mutationsmentioning

confidence: 99%

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Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Thakur

Kumar

Lee

et al. 2022

Genes

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“…Numerous variants in the LRRK2 have been reported; however, only some were associated with PD. At least seven variants (p.Arg1441Gly/Cys/His, p.Asn1437His, p.Gly2019Ser, p.Ile2020Thr, and p.Tyr1699Cys) are considered pathogenic, and a few others (p.Arg1628Pro, p.Gly2385Arg, and p.Ser1761Arg) are reported risk factors for PD ( Guadagnolo et al, 2021 ; Simpson et al, 2022 ; Dulski et al, forthcoming ). The most prevalent variant is p.Gly2019Ser, which alone may account for up 10–40% of the familial PD cases in the North African, Ashkenazi Jewish, and Mediterranean populations ( Mirelman et al, 2013 ; Marras et al, 2016 ; Trinh et al, 2018 ; Guadagnolo et al, 2021 ).…”

Section: Monogenic Forms Of Parkinson’s Diseasementioning

confidence: 99%

“…And while LRRK2 neuropathology typically reflects “usual” PD pathology, with prominent synuclein inclusions and nigral cell loss, there may be significant variability in neuropathological findings leading some patients to be reclassified atypical PD despite having usual clinical presentations ( Uitti et al, 2004 ). In summary, the LRRK2 mutations are most often associated with TD and GD subtypes ( Kim et al, 2012 ; Mirelman et al, 2013 ; Marras et al, 2016 ; Trinh et al, 2018 ; Madureira et al, 2020 ; Guadagnolo et al, 2021 ; Vinagre-Aragón et al, 2021 ; Lee et al, 2022 ; Simpson et al, 2022 ; Dulski et al, forthcoming ).…”

Section: Monogenic Forms Of Parkinson’s Diseasementioning

confidence: 99%

Genetic architecture of Parkinson’s disease subtypes – Review of the literature

Dulski

Uitti²,

Ross³

et al. 2022

Front. Aging Neurosci.

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The heterogeneity of Parkinson’s disease (PD) has been recognized since its description by James Parkinson over 200 years ago. The complexity of motor and non-motor PD manifestations has led to many attempts of PD subtyping with different prognostic outcomes; however, the pathophysiological foundations of PD heterogeneity remain elusive. Genetic contributions to PD may be informative in understanding the underpinnings of PD subtypes. As such, recognizing genotype-phenotype associations may be crucial for successful gene therapy. We review the state of knowledge on the genetic architecture underlying PD subtypes, discussing the monogenic forms, as well as oligo- and polygenic risk factors associated with various PD subtypes. Based on our review, we argue for the unification of PD subtyping classifications, the dichotomy of studies on genetic factors and genetic modifiers of PD, and replication of results from previous studies.

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Towards a Global View of Parkinson's Disease Genetics

Khani,

Cerquera‐Cleves,

Kekenadze

et al. 2024

Annals of Neurology

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Parkinson's disease (PD) is a global health challenge, yet historically studies of PD have taken place predominantly in European populations. Recent genetics research conducted in non‐European populations has revealed novel population‐specific genetic loci linked to PD risk, highlighting the importance of studying PD globally. These insights have broadened our understanding of PD etiology, which is crucial for developing disease‐modifying interventions. This review comprehensively explores the global genetic landscape of PD, emphasizing the scientific rationale for studying underrepresented populations. It underscores challenges, such as genotype–phenotype heterogeneity and inclusion difficulties for non‐European participants, emphasizing the ongoing need for diverse and inclusive research in PD. ANN NEUROL 2024

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Prevalence of ten LRRK2 variants in Parkinson's disease: A comprehensive review

Cited by 36 publications

References 173 publications

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade

Genetic architecture of Parkinson’s disease subtypes – Review of the literature

Towards a Global View of Parkinson's Disease Genetics

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