Comprehensive Analysis of Familial Parkinsonism Genes in Rapid‐Eye‐Movement Sleep Behavior Disorder

Mufti, Kheireddin; Rudakou, Uladzislau; Yu, Eric; Krohn, Lynne; Ruskey, Jennifer A.; Asayesh, Farnaz; Laurent, Sandra B.; Spiegelman, Dan; Arnulf, Isabelle; Hu, Michele T.M.; Montplaisir, Jacques; Gagnon, Jean François; Désautels, Alex; Dauvilliers, Yves; Gigli, Gian Luigi; Valente, Mariarosaria; Janes, Francesco; Högl, Birgit; Stefani, Ambra; Holzknecht, Evi; Šonka, Karel; Kemlink, David; Oertel, Wolfgang H.; Janzen, Annette; Plazzi, Giuseppe; Antelmi, Elena; Figorilli, Michela; Puligheddu, Monica; Mollenhauer, Brit; Trenkwalder, Claudia; Sixel‐Döring, Friederike; Cock, Valérie Cochen De; Monaca, Christelle; Heidbreder, Anna; Ferini‐Strambi, Luigi; Dijkstra, Femke; Viaene, Mineke; Abril, Beatriz; Boeve, Bradley F.; Postuma, Ronald B.; Rouleau, Guy A.

doi:10.1002/mds.28318

Cited by 12 publications

(6 citation statements)

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“…All samples and variants were filtered based on standard quality control process as previously reported ( 39 ). In brief, variants were separated into common and rare by minor allele frequency (MAF) in the cohort.…”

Section: Methodsmentioning

confidence: 99%

Clinical and Genetic Analysis of Costa Rican Patients With Parkinson's Disease

Torrealba‐Acosta

Prada

et al. 2021

Front. Neurol.

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Background: Most research in genomics of Parkinson's disease (PD) has been done in subjects of European ancestry, leading to sampling bias and leaving Latin American populations underrepresented. We sought to clinically characterize PD patients of Costa Rican origin and to sequence familial PD and atypical parkinsonism-associated genes in cases and controls.Methods: We enrolled 118 PD patients with 97 unrelated controls. Collected information included demographics, exposure to risk and protective factors, and motor and cognitive assessments. We sequenced coding and untranslated regions in familial PD and atypical parkinsonism-associated genes including GBA, SNCA, VPS35, LRRK2, GCH1, PRKN, PINK1, DJ-1, VPS13C, and ATP13A2.Results: Mean age of PD probands was 62.12 ± 13.51 years; 57.6% were male. The frequency of risk and protective factors averaged ~45%. Physical activity significantly correlated with better motor performance despite years of disease. Increased years of education were significantly associated with better cognitive function, whereas hallucinations, falls, mood disorders, and coffee consumption correlated with worse cognitive performance. We did not identify an association between tested genes and PD or any damaging homozygous or compound heterozygous variants. Rare variants in LRRK2 were nominally associated with PD; six were located between amino acids p.1620 and 1623 in the C-terminal-of-ROC (COR) domain of Lrrk2. Non-synonymous GBA variants (p.T369M, p.N370S, and p.L444P) were identified in three healthy individuals. One PD patient carried a pathogenic GCH1 variant, p.K224R.Discussion: This is the first study that describes sociodemographics, risk factors, clinical presentation, and genetics of Costa Rican patients with PD, adding information to genomics research in a Latino population.

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Section: Methodsmentioning

confidence: 99%

Clinical and Genetic Analysis of Costa Rican Patients With Parkinson's Disease

Torrealba‐Acosta

Prada

et al. 2021

Front. Neurol.

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“…There is evidence that these RBD and PD variants may be affecting gene expression differently, and in different brain regions, with RBD variants localised in cortical regions (Krohn et al, 2021). Additionally, prominent PD genes such as LRRK2 (Fernandez‐Santiago et al, 2016), MAPT , and autosomal recessive genes (Mufti, Rudakou, et al, 2021a) are not associated with isolated RBD. A similar pattern is found between RBD and DLB, where ALP genes SNCA , GBA , and TMEM175 are shared risk factors in both conditions, however, DLB genes APOE and BIN1 (Chia et al, 2021) are not associated with RBD (Gan‐Or et al, 2017; Krohn et al, 2021).…”

Section: Video‐polysomnography (V‐psg) As a Diagnostic Requirement An...mentioning

confidence: 99%

Rapid eye movement sleep behaviour disorder: Past, present, and future

Högl

Arnulf

Bergmann

et al. 2022

Journal of Sleep Research

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Summary This manuscript presents an overview of REM sleep behaviour disorder (RBD) with a special focus on European contributions. After an introduction examining the history of the disorder, we address the pathophysiological and clinical aspects, as well as the diagnostic issues. Further, implications of RBD diagnosis and biomarkers are discussed. Contributions of European researchers to this field are highlighted.

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“…PD carriers of these mutations often complain of insomnia, which increases their risk for dementia [ 4 , 5 ]. Evidence suggests that isolated rapid-eye-movement sleep behavior disorder (iRBD) may serve as a hallmark for prodromal synucleinopathy [ 6 ], while a decreased RBD risk is closely connected with the LRRK2 protective haplotype [ 7 ]. Sleep regulation has a strong genetic component [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

LRRK2 Deficiency Aggravates Sleep Deprivation-Induced Cognitive Loss by Perturbing Synaptic Pruning in Mice

Cheng

Zhang

et al. 2022

Brain Sciences

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Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are associated with pronounced sleep disorders or cognitive dysfunction in neurodegenerative diseases. However, the effects of LRRK2 deficiency on sleep rhythms and sleep deprivation-related cognitive changes, and the relevant underlying mechanism, remain unrevealed. In this study, Lrrk2-/- and Lrrk2+/+ mice were subjected to normal sleep (S) or sleep deprivation (SD). Sleep recording, behavioral testing, Golgi-cox staining, immunofluorescence, and real-time PCR were employed to evaluate the impacts of LRRK2 deficiency on sleep behaviors and to investigate the underlying mechanisms. The results showed that after SD, LRRK2-deficient mice displayed lengthened NREM and shortened REM, and reported decreased dendritic spines, increased microglial activation, and synaptic endocytosis in the prefrontal cortex. Meanwhile, after SD, LRRK2 deficiency aggravated cognitive impairments, especially in the recall memory cued by fear conditioning test. Our findings evidence that LRRK2 modulates REM/NREM sleep and its deficiency may exacerbate sleep deprivation-related cognitive disorders by perturbing synaptic plasticity and microglial synaptic pruning in mice.

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Comprehensive Analysis of Familial Parkinsonism Genes in Rapid‐Eye‐Movement Sleep Behavior Disorder

Cited by 12 publications

References 39 publications

Clinical and Genetic Analysis of Costa Rican Patients With Parkinson's Disease

Clinical and Genetic Analysis of Costa Rican Patients With Parkinson's Disease

Rapid eye movement sleep behaviour disorder: Past, present, and future

LRRK2 Deficiency Aggravates Sleep Deprivation-Induced Cognitive Loss by Perturbing Synaptic Pruning in Mice

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