Clinical Correlations With Lewy Body Pathology in<i>LRRK2</i>-Related Parkinson Disease

Kalia, Lorraine V.; Lang, Anthony E.; Hazrati, Lili Naz; Fujioka, Shinsuke; Wszołek, Zbigniew K.; Dickson, Dennis W.; Ross, Owen A.; Deerlin, Vivianna M. Van; Trojanowski, John Q.; Hurtig, Howard I.; Alcalay, Roy N.; Marder, Karen; Clark, Lorraine N.; Gaig, Carles; Tolosa, Eduardo; Ruíz‐Martínez, Javier; Martí-Massó, J.F.; Ferrer, Isidre; Munáin, Adolfo López de; Goldman, Samuel; Schüle, Birgitt; Langston, J. William; Aasly, Jan; Giordana, Maria Teresa; Bonifati, Vincenzo; Puschmann, Andreas; Canesi, Margherita; Pezzoli, Gianni; Paula, André Maues De; Hasegawa, Kazuko; Duyckaerts, Charles; Brice, Alexis; Stoessl, A. Jon; Marras, Connie

doi:10.1001/jamaneurol.2014.2704

Cited by 289 publications

(272 citation statements)

References 21 publications

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“…Still, mounting evidence suggests that certain non-motor symptoms such as cognitive decline, smell loss or dysautonomia may be less prominent. Recently, a clinicopathological study in G2019S LRRK2-PD suggested that those cases without Lewy bodies have less non-motor symptoms 5. The absence in our case of αSyn aggregates is in agreement with this since our patient had normal sense of smell and little dysautonomia.…”

Section: Discussionsupporting

confidence: 90%

Lack of central and peripheral nervous system synuclein pathology in R1441G LRRK2-associated Parkinson’s disease

Vilas

Gelpí

Aldecoa

et al. 2018

J Neurol Neurosurg Psychiatry

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Section: Discussionsupporting

confidence: 90%

Lack of central and peripheral nervous system synuclein pathology in R1441G LRRK2-associated Parkinson’s disease

Vilas

Gelpí

Aldecoa

et al. 2018

J Neurol Neurosurg Psychiatry

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“…LRRK2 pathogenic mutation carriers with PD have generally displayed clinical characteristics similar to that of idiopathic PD, however neuropathological findings have varied considerably [24], suggesting that these mutations may cause a wider range of phenotypes other than just PD. Indeed, LRRK2 has been studied in a wide range of neurodegenerative disorders, with a small number of pathogenic mutation carriers identified in progressive supranuclear palsy (p.R1441H) [25], corticobasal syndrome (p.G2019S) [26], frontotemporal lobar degeneration with ubiquitinated neuronal cytoplasmic inclusions (p.G2019S) [27], and dementia and AD (p.Y1699C, p.G2019S).…”

Section: Discussionmentioning

confidence: 99%

LRRK2 variation and dementia with Lewy bodies

Heckman

Soto‐Ortolaza

Sanchez‐Contreras

et al. 2016

Parkinsonism & Related Disorders

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Introduction The leucine-rich repeat kinase 2 (LRRK2) gene contains several variants that cause Parkinson's disease (PD) and others that modify PD risk. However, little is known about the role of LRRK2 in dementia with Lewy bodies (DLB). Aims of this study were to screen DLB patients for pathogenic LRRK2 variants and to evaluate associations between common LRRK2 variants and risk of DLB. Methods 417 clinical DLB patients and 1,790 controls were included in the primary analysis. Additionally, 355 Lewy body disease patients assessed as having a high likelihood of clinical DLB based on neuropathological findings were included in secondary analysis. Seven pathogenic LRRK2 variants were assessed in patients, while 17 common LRRK2 exonic variants and 1 GWAS-nominated common LRRK2 PD-risk variant were evaluated for association with DLB. Results We identified carriers of 2 different pathogenic LRRK2 variants. One clinical DLB patient was a p.G2019S carrier, while in the pathological high likelihood DLB series there was one carrier of the p.R1441C mutation. However, examination of clinical records revealed the p.R1441C carrier to have PD with dementia. Evaluation of common variants did not reveal any associations with DLB risk after multiple testing adjustment. However, a non-significant trend similar to that previously reported for PD was observed for the protective p.N551K-R1398H-K1423K haplotype in the clinical DLB series (OR: 0.76, P=0.061). Conclusion LRRK2 does not appear to play a major role in DLB, however further study of p.G2019S and the p.N551K-R1398H-K1423K haplotype is warranted to better understand their involvement in determining DLB risk.

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“…Another clinical feature implicated in PD is the abnormal accumulation of a-synuclein in protein aggregates within Lewy bodies (Baba et al, 1998;Chung et al, 2001;Farrer et al, 2001;Kalia et al, 2015). First, SNCA mRNA expression changes were determined by qPCR with further prolonged culture of mDA neurons at days 28, 35, 42, and 49 ( Figure 3A).…”

Section: Differentiation Of Midbrain Dopaminergic Neurons From Human mentioning

confidence: 99%

Molecular Features Underlying Neurodegeneration Identified through In Vitro Modeling of Genetically Diverse Parkinson’s Disease Patients

et al. 2016

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The fact that Parkinson's disease (PD) can arise from numerous genetic mutations suggests a unifying molecular pathology underlying the various genetic backgrounds. To address this hypothesis, we took an integrated approach utilizing in vitro disease modeling and comprehensive transcriptome profiling to advance our understanding of PD progression and the concordant downstream signaling pathways across divergent genetic predispositions. To model PD in vitro, we generated neurons harboring disease-causing mutations from patient-specific, induced pluripotent stem cells (iPSCs). We observed signs of degeneration in midbrain dopaminergic neurons, reflecting the cardinal feature of PD. Gene expression signatures of PD neurons provided molecular insights into disease phenotypes observed in vitro, including oxidative stress vulnerability and altered neuronal activity. Notably, PD neurons show that elevated RBFOX1, a gene previously linked to neurodevelopmental diseases, underlies a pattern of alternative RNA-processing associated with PD-specific phenotypes.

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Clinical Correlations With Lewy Body Pathology inLRRK2-Related Parkinson Disease

Cited by 289 publications

References 21 publications

Lack of central and peripheral nervous system synuclein pathology in R1441G LRRK2-associated Parkinson’s disease

Lack of central and peripheral nervous system synuclein pathology in R1441G LRRK2-associated Parkinson’s disease

LRRK2 variation and dementia with Lewy bodies

Molecular Features Underlying Neurodegeneration Identified through In Vitro Modeling of Genetically Diverse Parkinson’s Disease Patients

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