The role of SNCA and MAPT in <scp>P</scp>arkinson disease and LRRK2 parkinsonism in the <scp>T</scp>unisian <scp>A</scp>rab‐<scp>B</scp>erber population

Trinh, Joanne; Guella, Ilaria; Vilariño‐Güell, Carles; Evans, David A.; Encarnacion, Mary Joy; Sherman, Holly E.; Hentati, Fayçal; Farrer, Matthew J.

doi:10.1111/ene.12489

Cited by 10 publications

(18 citation statements)

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“…We first examined the scenario of a 39‐year‐old, male carrier of a wild‐type SNCA triplication from the ‘Iowa kindred’ (Singleton et al ., ; Farrer et al ., ; Gwinn et al ., ; Trinh et al ., ).…”

Section: Resultsmentioning

confidence: 97%

“…Accounting for changes in age ( T ), we can thus predict the time of clinically diagnosed parkinsonism in this proband at age 41.7 years (as defined by P R = 100%; Fig. ), which would be consistent with insights from a recently published meta‐analysis for the AOO in pathogenic SNCA genotypes (Trinh et al ., ).…”

Section: Resultsmentioning

confidence: 97%

“…Similarly, a 70‐year‐old Japanese man carrying a duplication of the wild‐type SNCA allele on one sister chromatid ( n = 3 SNCA alleles; D = 0.75; I = 0.5) (Nishioka et al ., ) with no known significant exposure to an environmental risk factor associated with PD ( E = 0.02 adjusted for age; Table ) will have a P R score of (0.02( E ) + 0.75( D ) + 0.5( I )) × 1.2( G ) × 70( T ) = 106.68%. According to the formula, this man is expected to have expressed his typical PD phenotype by the age of 65.62 years ( P R = 100%) (Trinh et al ., ). Entering a higher value for E (if he had also been exposed to identifiable, PD‐associated risk factors during adulthood) would increase his P R score, and thus, measurably lower this man's AOO, and by inference, the time of diagnosis.…”

Section: Resultsmentioning

confidence: 97%

“…Carrier status of a heterozygous mutation at the PARK‐ LRRK2 locus at few select codons (Marras et al ., ) is currently considered the second most frequent, genetic risk factor for late‐onset, sporadic PD (after GBA variants) with an estimated, mean prevalence rate of 1–2% in North America (Lesage et al ., ; Ozelius et al ., ; Heckman et al ., ; Bozi et al ., ; Trinh et al ., ; Kang & Marto, ). Mutations in the LRRK2 gene had been initially identified as the cause of rare, dominantly inherited, familial PD in multiple pedigrees (Paisan‐Ruiz et al ., ; Zimprich et al ., ), but many questions surrounding the causative mechanisms by which bona fide LRRK2 mutants promote brain pathology (either directly, or indirectly) at an overall lower than the expected penetrance rate have remained unanswered.…”

Section: Resultsmentioning

confidence: 98%

“…Locascio et al ., ) and a likely reversed sex bias in LRRK2 ‐associated illnesses. The latter was recently identified in human PD cohort studies (Cilia et al ., ; Trinh et al ., ; Marder et al ., ). In our formula, the variable ‘sex’ is entered as the independent factor ‘ G ’; it is expected to reflect the contribution of genetic elements (biological sex) and their interaction with environmental elements that may differ between the sexes (gender).…”

Section: Methodsmentioning

confidence: 98%

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Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the P_REDIGT score

Schlossmacher

Tomlinson

Santos

et al. 2016

Eur J of Neuroscience

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Fifty-five years after the concept of dopamine replacement therapy was introduced, Parkinson disease (PD) remains an incurable neurological disorder. To date, no disease-modifying therapeutic has been approved. The inability to predict PD incidence risk in healthy adults is seen as a limitation in drug development, because by the time of clinical diagnosis ≥ 60% of dopamine neurons have been lost. We have designed an incidence prediction model founded on the concept that the pathogenesis of PD is similar to that of many disorders observed in ageing humans, i.e. a complex, multifactorial disease. Our model considers five factors to determine cumulative incidence rates for PD in healthy adults: (i) DNA variants that alter susceptibility (D), e.g. carrying a LRRK2 or GBA risk allele; (ii) Exposure history to select environmental factors including xenobiotics (E); (iii) Gene-environment interactions that initiate pathological tissue responses (I), e.g. a rise in ROS levels, misprocessing of amyloidogenic proteins (foremost, a-synuclein) and dysregulated inflammation; (iv) sex (or gender; G); and importantly, (v) time (T) encompassing ageing-related changes, latency of illness and propagation of disease. We propose that cumulative incidence rates for PD (P R ) can be calculated in healthy adults, using the formula: P R (%) = (E + D + I) 9 G 9 T. Here, we demonstrate six case scenarios leading to young-onset parkinsonism (n = 3) and late-onset PD (n = 3). Further development and validation of this prediction model and its scoring system promise to improve subject recruitment in future intervention trials. Such efforts will be aimed at disease prevention through targeted selection of healthy individuals with a higher prediction score for developing PD in the future and at disease modification in subjects that already manifest prodromal signs.

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Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 98%

See 3 more Smart Citations

Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the P_REDIGT score

Schlossmacher

Tomlinson

Santos

et al. 2016

Eur J of Neuroscience

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LRRK2 and Parkinson's disease: from genetics to targeted therapy

Sosero

Gan‐Or

2023

Ann Clin Transl Neurol

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LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence of Lewy bodies and marked Alzheimer's disease pathology. The mechanisms underlying LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested, among others. As novel therapies targeting LRRK2 are under development, understanding the role and function of LRRK2 in PD is becoming increasingly important. Here, we outline the epidemiological, pathophysiological, and clinical features of LRRK2-PD, and discuss the arising therapeutic approaches targeting LRRK2 and possible future directions for research.

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Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Lai¹,

Alipanahi²,

Fontanillas³

et al. 2021

Annals of Neurology

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ObjectiveThe aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age‐at‐onset of Parkinson's disease.MethodsWe performed the first genomewide association study of penetrance and age‐at‐onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non‐cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age‐at‐onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age‐at‐onset in LRRK2 mutation carriers.ResultsA variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E‐08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co‐immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E‐07; age‐at‐onset top variant: p value = 9.3E‐07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age‐at‐onset.InterpretationThis study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations. ANN NEUROL 2021;90:82–94

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The role of SNCA and MAPT in Parkinson disease and LRRK2 parkinsonism in the Tunisian Arab‐Berber population

Cited by 10 publications

References 8 publications

Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the P_REDIGT score

Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the P_REDIGT score

LRRK2 and Parkinson's disease: from genetics to targeted therapy

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

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The role of SNCA and MAPT in Parkinson disease and LRRK2 parkinsonism in the Tunisian Arab‐Berber population

Cited by 10 publications

References 8 publications

Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the PREDIGT score

Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the PREDIGT score

LRRK2 and Parkinson's disease: from genetics to targeted therapy

Genomewide Association Studies of LRRK2 Modifiers of Parkinson's Disease

Contact Info

Product

Resources

About

Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the P_REDIGT score

Modelling idiopathic Parkinson disease as a complex illness can inform incidence rate in healthy adults: the P_REDIGT score