Dataset Information

A comprehensive screening of copy number variability in dementia with Lewy bodies.

ABSTRACT: The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk.

SUBMITTER: Kun-Rodrigues C

PROVIDER: S-EPMC6541211 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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A comprehensive screening of copy number variability in dementia with Lewy bodies.

Kun-Rodrigues Celia C Orme Tatiana T Carmona Susana S Hernandez Dena G DG Ross Owen A OA Eicher John D JD Shepherd Claire C Parkkinen Laura L Darwent Lee L Heckman Michael G MG Scholz Sonja W SW Troncoso Juan C JC Pletnikova Olga O Dawson Ted T Rosenthal Liana L Ansorge Olaf O Clarimon Jordi J Lleo Alberto A Morenas-Rodriguez Estrella E Clark Lorraine L Honig Lawrence S LS Marder Karen K Lemstra Afina A Rogaeva Ekaterina E St George-Hyslop Peter P Londos Elisabet E Zetterberg Henrik H Barber Imelda I Braae Anne A Brown Kristelle K Morgan Kevin K Troakes Claire C Al-Sarraj Safa S Lashley Tammaryn T Holton Janice J Compta Yaroslau Y Van Deerlin Vivianna V Serrano Geidy E GE Beach Thomas G TG Lesage Suzanne S Galasko Douglas D Masliah Eliezer E Santana Isabel I Pastor Pau P Diez-Fairen Monica M Aguilar Miquel M Tienari Pentti J PJ Myllykangas Liisa L Oinas Minna M Revesz Tamas T Lees Andrew A Boeve Brad F BF Petersen Ronald C RC Ferman Tanis J TJ Escott-Price Valentina V Graff-Radford Neill N Cairns Nigel J NJ Morris John C JC Pickering-Brown Stuart S Mann David D Halliday Glenda M GM Hardy John J Trojanowski John Q JQ Dickson Dennis W DW Singleton Andrew A Stone David J DJ Guerreiro Rita R Bras Jose J

Neurobiology of aging 20181024

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to f ...[more]

PMID: 30448004

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Project description:Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X-linked Parkinson's disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha-Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined. Here, analysis of the spatial distribution and expression of RAB39B was conducted in post-mortem human brain tissue from cases of dementia with Lewy bodies (DLB, n = 10), Alzheimer's disease (AD, n = 12) and controls (n = 12). Assessment of cortical RAB39B immunoreactivity using tissue microarrays revealed an overall reduction in the area of RAB39B positive gray matter in DLB cases when compared to controls and AD cases. Strikingly, RAB39B co-localized with beta-amyloid (Aβ) plaques in all cases examined and was additionally present in a subpopulation of Lewy bodies (LBs) in DLB. Biochemical measures of total RAB39B levels within the temporal cortex were unchanged between DLB, AD and controls. However, upon subcellular fractionation, a reduction of RAB39B in the cytoplasmic pool was found in DLB cases, alongside an increase of phosphorylated aSyn and Aβ in whole tissue lysates. The reduction of cytoplasmic RAB39B is consistent with an impaired reserve capacity for RAB39B-associated functions, which in turn may facilitate LB aggregation and synaptic impairment. Collectively, our data support the involvement of RAB39B in the pathogenesis of DLB and the co-aggregation of RAB39B with Aβ in plaques suggests that age-associated cerebral Aβ pathology may be contributory to the loss of RAB39B. Thus RAB39B, its associated functional pathways and its entrapment in aggregates may be considered as future targets for therapeutic interventions to impede the overall pathological burden and cellular dysfunction in Lewy body diseases.

Dataset Information

A comprehensive screening of copy number variability in dementia with Lewy bodies.

Publications

A comprehensive screening of copy number variability in dementia with Lewy bodies.

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