LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study

Grochowska, Martyna M; Masius, Roy; Geut, Hanneke; Breedveld, Guido J.; Kuipers, Demy J.S.; Minneboo, Michelle; Mascaro, Ana Carreras; Yonova-Doing, Ekaterina; Simons, Erik J.; Zhao, Tianna; Fonzo, Alessio; Parchi, Piero; Melis, Marta; Brouwer, Rutger W. W.; Heijsman, Daphne; Ingrassia, Angela; Calandra-Buonaura, Giovanna; Rozemüller, Annemieke; Sarchioto, Marianna; Olgiati, Simone; Hoogers, Susanne E; Ghazvini, Mehrnaz; IJpma, Arne; IJcken, Wilfred F. J. van; Nicholl, David; Majoor‐Krakauer, Danielle; Cossu, Giovanni; Berg, Wilma D.J. Van de; Bonifati, Vincenzo; Quadri, Marialuisa; Mandemakers, Wim; Kievit, Anneke J.A.; Boon, Agnita J.W.; Rood, Janneke P.A; Vergouw, Leonie J.M.; Jong, Frank Jan de; Swieten, John C. van; Mattace‐Raso, Francesco; Leenders, Klaus L.; Ferreira, Joaquim J.; Guedes, Leonor Correia; Puschmann, Andreas; Ygland, Emil; Nilsson, Christer; Chien, Hsin Fen; Barbosa, Egberto Reis; Jardim, Laura Bannach; Rieder, Carlos Roberto de Mello; Chang, Hsiu‐Chen; Lu, Chin‐Song; Wu-Chou, Yah-Huei; Yeh, Tu-Hsueh; Lopiano, Leonardo; Tassorelli, Cristina; Pacchetti, C.; Riboldazzi, Giulio; Bono, Giorgio; Comi, Cristoforo; Padovani, Alessandro; Borroni, Barbara; Raudino, Francesco; Fincati, E.; Tinazzi, Michèle; Bonizzato, Alberto; Ferracci, C; Libera, A. Dalla; Abbruzzese, Giovanni; Cortelli, Pietro; Capellari, Sabina; Marconi, Roberto; Guidi, Marco; Onofrj, Marco; Thomas, Astrid; Vanacore, Nicola; Meco, Giuseppe; Fabrizio, Edito; Fabbrini, Giovanni; Berardelli, Alfredo; Stocchi, Fabrizio; Vacca, Laura; Barone, Paolo; Picillo, Marina; Michele, Giuseppe De; Criscuolo, Chiara; Mari, Michele; Dell’Aquila, Claudia; Iliceto, Gianni; Toni, Vincenzo; Trianni, Giorgio; Gagliardi, Monica; Annesi, Grazia; Quattrone, Aldo; Saddi, Valeria; Cossu, Gianni; Melis, Maurizio

doi:10.1016/s1474-4422(18)30179-0

Cited by 110 publications

(109 citation statements)

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“…Mitochondrial homeostasis is known to be influenced by aSyn, which interacts with mitochondria-associated ER membranes, and is suggested to play a role in disrupting autophagy, endosomal transport, and ER traffic to the Golgi 31 . Furthermore, the recently described novel pathogenic variant in LRP-10 described in Donor B-PD has been linked to disturbance of intracellular membrane trafficking in PD 32 . Our finding that mitochondria co-localize with membrane fragments and membranous features reminiscent of autophagosomes within LB, supports the hypothesis that dysregulation of intracellular degradation pathways for proteins and entire organelles and disturbed intracellular membrane trafficking is a determining factor in PD.…”

Section: Discussionmentioning

confidence: 99%

“…No listed known causative genetic variants were detected in the donors. In Donor B-PD, a variant in the LRP-10 gene, a potential new gene causal for PD that needs yet to be confirmed by others, as previously described 32 . Variants were to be reported if they fulfilled the following four criteria: (1) Variant(s) located within the following list of genes associated with PD or Parkinsonian syndromes: ATP13A2; ATP6AP2; CHCHD2; DNAJC13; DNAJC6; EIF4G1; FBXO7; GBA; LRRK2; PARK2; PARK7; PINK1; PLA2G6; RAB39B; SNCA; SYNJ1; TARDBP; VPS35; VPS13C; MAPT; GRN; TMEM230; POLG; DCTN1; PTRHD1.…”

Section: Whole Exome Sequencing and Pd Gene Analysismentioning

confidence: 92%

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Lewy pathology in Parkinson’s disease consists of a crowded organellar, membranous medley

Sharamoradian¹,

Britschgi

Stahlberg³

et al. 2017

Preprint

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SummaryParkinson’s disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites, which are neuronal inclusions that are immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of this Lewy pathology is crucial to understanding pathogenesis and progression of the disease. Using correlative light and electron microscopy/tomography on brain tissue from five Parkinson’s disease brain donors, we identified α-synuclein immunopositive Lewy pathology and could show that the majority of these features including Lewy bodies and Lewy neurites primarily consists of a crowded membranous medley of vesicular structures and dysmorphic organelles. Only a small fraction of observed Lewy bodies contained predominant proteinaceous filaments, as previously described. The crowding of organellar components was confirmed by STED- based super-resolution microscopy, and high lipid content within the α-synuclein immunopositive inclusions was corroborated by confocal imaging, CARS/FTIR imaging and lipidomics. Applying this correlative high-resolution imaging and biophysical approach, we discovered in the postmortem brain of Parkinson’s patients a subcellular protein-lipid compartmentalization not previously described in Lewy pathology.

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Section: Discussionmentioning

confidence: 99%

Section: Whole Exome Sequencing and Pd Gene Analysismentioning

confidence: 92%

Lewy pathology in Parkinson’s disease consists of a crowded organellar, membranous medley

Sharamoradian¹,

Britschgi

Stahlberg³

et al. 2017

Preprint

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“…LRP12 and ITGA8 were also identified as hits from our screen. LRP12 belongs to the same family as LRP10, a gene encoding a low-density lipoprotein receptor-related protein that has been found to carry risk variants in patients with PD (Quadri et al, 2018). Previously published genetic analyses have already implicated ITGA8 in the pathogenesis of PD.…”

Section: Discussionmentioning

confidence: 99%

An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of a-synuclein

Kara

Crimi

Wiedmer

et al. 2019

Preprint

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Neuropathological and experimental evidence suggests that the cell-to-cell transfer of a-synuclein has an important role in the pathogenesis of Parkinson's disease (PD). However, the mechanism underlying this phenomenon is not fully understood. We undertook an siRNA, genome-wide high throughput screen to identify genes regulating the cell-to-cell transfer of a-synuclein. We transiently transfected HEK cells stably overexpressing a-synuclein with a construct encoding GFP-2a-aSynuclein-RFP. The cells expressing a-synuclein-RFP through transfection were double positive for GFP and RFP fluorescence, whereas the cells receiving it through transfer were positive only for RFP fluorescence. The amount of asynuclein transfer was quantified by high content microscopy. A series of unbiased screens confirmed the involvement of 38 genes in the regulation of a-synuclein-RFP transfer. One of those hits was ITGA8, a candidate gene recently identified through a large PD genome wide association study (GWAS). Weighted gene co-expression network analysis (WGCNA) and weighted protein-protein network interaction analysis (WPPNIA) showed that the hits clustered in networks that included known PD Mendelian and GWAS risk genes more frequently than expected than random chance. Given the genetic overlap between a-synuclein transfer and PD, those findings provide supporting evidence for the importance of the cell-to-cell transfer of a-synuclein in the pathogenesis of PD, and expand our understanding of the mechanism of a-synuclein spread.

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“…Genomic DNA of the probands and all available family members was isolated from peripheral leukocytes using standard protocols. Exon regions and exon–intron boundaries of the LRP10 gene (NM_014045) were amplified with polymerase chain reaction (PCR) primers as previously described . Variants that fulfill the following criteria were included for further analysis: (1) the variant being present in the heterozygous state; (2) rarity defined as a minor allele frequency lower than 0.001 in the 1000 Genome Project, the National Heart, Lung, and Blood Institute's Exome Sequencing Project exome variant server, the Exome Aggregation Consortium, and the Genome Aggregation Database (GnomAD); (3) exonic and nonsynonymous or annotated as “splice donor,” “splice acceptor,” or “splice region” in the GnomAD database; and (4) pathogenicity, that is, all nonsense mutations and indels were regarded as disease causing; splicing mutations were only included when predicted to affect splicing at least 2 of 4 in silico tools, that is, Human Splicing Finder, MaxEntScan, dbscSNV, and SPIDEX; missense variants were only considered causative when they were predicted to be disease causing by at least 5 of 11 in silico tools as previously described .…”

Section: Methodsmentioning

confidence: 99%

“…Mutations in the LRP10 (low‐density lipoprotein receptor‐related protein 10) gene have been identified recently in individuals affected by PD, Parkinson's disease dementia, and dementia with Lewy bodies, which are thought to be parts of a continuum of Lewy body diseases . Initially, Quadri and colleagues found a heterozygous LRP10 missense mutation (c.1807G>A, p.G603R) that cosegregated with the disease in a large Italian family with dominantly inherited PD. Further screening in an international cohort of 660 probands revealed additional mutations (2 indels, 4 missense, and 2 splicing mutations) in 8 unrelated individuals (4 with familial PD, 2 with PD dementia, and 2 with dementia with Lewy bodies).…”

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confidence: 99%

LRP10 in autosomal‐dominant Parkinson's disease

et al. 2019

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Background Recently, the LRP10 gene has been identified as a novel genetic cause in individuals affected by Parkinson's disease (PD), Parkinson's disease dementia, or dementia with Lewy bodies. Objective We investigated the involvement of LRP10 mutations in Chinese patients with familial PD and reviewed previous studies of LRP10 mutations in patients with PD. Methods A mutation analysis of the LRP10 gene was performed in a cohort of 205 unrelated Chinese patients with familial PD. Burden analysis was conducted using data from the Genome Aggregation Database and 5 genetic studies of LRP10 in patients with PD (including our cohort). Results A total of 3 novel potentially pathogenic variants, c.32T>A (p.L11H), c.1184G>A (p.R395H), and c.1333G>A (p.A445T), were detected in 3 probands of our cohort. However, burden analysis argued against an overrepresentation of variant alleles in patients with PD. Conclusions Genetic screening of the LRP10 gene in our cohort may provide independent, albeit limited, evidence for the pathogenicity of LRP10 in familial PD. Burden analysis using data from current studies failed to support the association between LRP10 and PD in general. Thus, more robust replication studies are warranted to determine the involvement of LRP10 in the pathogenesis of PD. © 2019 International Parkinson and Movement Disorder Society

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LRP10 genetic variants in familial Parkinson's disease and dementia with Lewy bodies: a genome-wide linkage and sequencing study

Cited by 110 publications

References 40 publications

Lewy pathology in Parkinson’s disease consists of a crowded organellar, membranous medley

Lewy pathology in Parkinson’s disease consists of a crowded organellar, membranous medley

An integrated genomic approach to dissect the genetic landscape regulating the cell-to-cell transfer of a-synuclein

LRP10 in autosomal‐dominant Parkinson's disease

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