Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations.
Identifieur interne : 000421 ( PubMed/Curation ); précédent : 000420; suivant : 000422Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations.
Auteurs : Roy N. Alcalay [États-Unis] ; Oren A. Levy [États-Unis] ; Cheryl C. Waters [États-Unis] ; Stanley Fahn [États-Unis] ; Blair Ford [États-Unis] ; Sheng-Han Kuo [États-Unis] ; Pietro Mazzoni [États-Unis] ; Michael W. Pauciulo [États-Unis] ; William C. Nichols [États-Unis] ; Ziv Gan-Or [Canada] ; Guy A. Rouleau [Canada] ; Wendy K. Chung [États-Unis] ; Pavlina Wolf [États-Unis] ; Petra Oliva [États-Unis] ; Joan Keutzer [États-Unis] ; Karen Marder [États-Unis] ; Xiaokui Zhang [États-Unis]Source :
- Brain : a journal of neurology [ 1460-2156 ] ; 2015.
English descriptors
- KwdEn :
- Aged, Cohort Studies, Female, Gene Expression Regulation, Enzymologic (genetics), Genotype, Glucosylceramidase (genetics), Glucosylceramidase (metabolism), Humans, Jews (genetics), Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Mutation (genetics), Parkinson Disease (enzymology), Parkinson Disease (genetics), Protein-Serine-Threonine Kinases (genetics), Severity of Illness Index.
- MESH :
- chemical , genetics : Glucosylceramidase, Protein-Serine-Threonine Kinases.
- enzymology : Parkinson Disease.
- genetics : Gene Expression Regulation, Enzymologic, Jews, Mutation, Parkinson Disease.
- chemical , metabolism : Glucosylceramidase.
- Aged, Cohort Studies, Female, Genotype, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Male, Middle Aged, Severity of Illness Index.
Abstract
Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 µmol/l/h, versus 12.11 µmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 µmol/l/h versus 11.93 µmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target.
DOI: 10.1093/brain/awv179
PubMed: 26117366
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<author><name sortKey="Kuo, Sheng Han" sort="Kuo, Sheng Han" uniqKey="Kuo S" first="Sheng-Han" last="Kuo">Sheng-Han Kuo</name>
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<author><name sortKey="Gan Or, Ziv" sort="Gan Or, Ziv" uniqKey="Gan Or Z" first="Ziv" last="Gan-Or">Ziv Gan-Or</name>
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<author><name sortKey="Chung, Wendy K" sort="Chung, Wendy K" uniqKey="Chung W" first="Wendy K" last="Chung">Wendy K. Chung</name>
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<author><name sortKey="Marder, Karen" sort="Marder, Karen" uniqKey="Marder K" first="Karen" last="Marder">Karen Marder</name>
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<author><name sortKey="Zhang, Xiaokui" sort="Zhang, Xiaokui" uniqKey="Zhang X" first="Xiaokui" last="Zhang">Xiaokui Zhang</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations.</title>
<author><name sortKey="Alcalay, Roy N" sort="Alcalay, Roy N" uniqKey="Alcalay R" first="Roy N" last="Alcalay">Roy N. Alcalay</name>
<affiliation wicri:level="1"><nlm:affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA rna2104@columbia.edu.</nlm:affiliation>
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<author><name sortKey="Levy, Oren A" sort="Levy, Oren A" uniqKey="Levy O" first="Oren A" last="Levy">Oren A. Levy</name>
<affiliation wicri:level="1"><nlm:affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY</wicri:regionArea>
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<author><name sortKey="Waters, Cheryl C" sort="Waters, Cheryl C" uniqKey="Waters C" first="Cheryl C" last="Waters">Cheryl C. Waters</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY</wicri:regionArea>
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<author><name sortKey="Fahn, Stanley" sort="Fahn, Stanley" uniqKey="Fahn S" first="Stanley" last="Fahn">Stanley Fahn</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY</wicri:regionArea>
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<author><name sortKey="Ford, Blair" sort="Ford, Blair" uniqKey="Ford B" first="Blair" last="Ford">Blair Ford</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY</wicri:regionArea>
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<author><name sortKey="Kuo, Sheng Han" sort="Kuo, Sheng Han" uniqKey="Kuo S" first="Sheng-Han" last="Kuo">Sheng-Han Kuo</name>
<affiliation wicri:level="1"><nlm:affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY</wicri:regionArea>
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<author><name sortKey="Mazzoni, Pietro" sort="Mazzoni, Pietro" uniqKey="Mazzoni P" first="Pietro" last="Mazzoni">Pietro Mazzoni</name>
<affiliation wicri:level="1"><nlm:affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY</wicri:regionArea>
</affiliation>
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<author><name sortKey="Pauciulo, Michael W" sort="Pauciulo, Michael W" uniqKey="Pauciulo M" first="Michael W" last="Pauciulo">Michael W. Pauciulo</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics; University of Cincinnati College of Medicine, Cincinnati, OH</wicri:regionArea>
</affiliation>
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<author><name sortKey="Nichols, William C" sort="Nichols, William C" uniqKey="Nichols W" first="William C" last="Nichols">William C. Nichols</name>
<affiliation wicri:level="1"><nlm:affiliation>3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics; University of Cincinnati College of Medicine, Cincinnati, OH, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics; University of Cincinnati College of Medicine, Cincinnati, OH</wicri:regionArea>
</affiliation>
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<author><name sortKey="Gan Or, Ziv" sort="Gan Or, Ziv" uniqKey="Gan Or Z" first="Ziv" last="Gan-Or">Ziv Gan-Or</name>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea>4 Montréal Neurological Institute and Hospital, McGill University, Montreal, QC</wicri:regionArea>
</affiliation>
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<author><name sortKey="Rouleau, Guy A" sort="Rouleau, Guy A" uniqKey="Rouleau G" first="Guy A" last="Rouleau">Guy A. Rouleau</name>
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<country xml:lang="fr">Canada</country>
<wicri:regionArea>4 Montréal Neurological Institute and Hospital, McGill University, Montreal, QC</wicri:regionArea>
</affiliation>
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<author><name sortKey="Chung, Wendy K" sort="Chung, Wendy K" uniqKey="Chung W" first="Wendy K" last="Chung">Wendy K. Chung</name>
<affiliation wicri:level="1"><nlm:affiliation>5 Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>5 Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY</wicri:regionArea>
</affiliation>
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<author><name sortKey="Wolf, Pavlina" sort="Wolf, Pavlina" uniqKey="Wolf P" first="Pavlina" last="Wolf">Pavlina Wolf</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Oliva, Petra" sort="Oliva, Petra" uniqKey="Oliva P" first="Petra" last="Oliva">Petra Oliva</name>
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<country xml:lang="fr">États-Unis</country>
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</affiliation>
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<author><name sortKey="Keutzer, Joan" sort="Keutzer, Joan" uniqKey="Keutzer J" first="Joan" last="Keutzer">Joan Keutzer</name>
<affiliation wicri:level="1"><nlm:affiliation>6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA</wicri:regionArea>
</affiliation>
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<author><name sortKey="Marder, Karen" sort="Marder, Karen" uniqKey="Marder K" first="Karen" last="Marder">Karen Marder</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 7 Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Zhang, Xiaokui" sort="Zhang, Xiaokui" uniqKey="Zhang X" first="Xiaokui" last="Zhang">Xiaokui Zhang</name>
<affiliation wicri:level="1"><nlm:affiliation>6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA</wicri:regionArea>
</affiliation>
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<term>Cohort Studies</term>
<term>Female</term>
<term>Gene Expression Regulation, Enzymologic (genetics)</term>
<term>Genotype</term>
<term>Glucosylceramidase (genetics)</term>
<term>Glucosylceramidase (metabolism)</term>
<term>Humans</term>
<term>Jews (genetics)</term>
<term>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Mutation (genetics)</term>
<term>Parkinson Disease (enzymology)</term>
<term>Parkinson Disease (genetics)</term>
<term>Protein-Serine-Threonine Kinases (genetics)</term>
<term>Severity of Illness Index</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Glucosylceramidase</term>
<term>Protein-Serine-Threonine Kinases</term>
</keywords>
<keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Parkinson Disease</term>
</keywords>
<keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Gene Expression Regulation, Enzymologic</term>
<term>Jews</term>
<term>Mutation</term>
<term>Parkinson Disease</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Glucosylceramidase</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Aged</term>
<term>Cohort Studies</term>
<term>Female</term>
<term>Genotype</term>
<term>Humans</term>
<term>Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</term>
<term>Male</term>
<term>Middle Aged</term>
<term>Severity of Illness Index</term>
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<front><div type="abstract" xml:lang="en">Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 µmol/l/h, versus 12.11 µmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 µmol/l/h versus 11.93 µmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target.</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26117366</PMID>
<DateCreated><Year>2015</Year>
<Month>08</Month>
<Day>25</Day>
</DateCreated>
<DateCompleted><Year>2015</Year>
<Month>11</Month>
<Day>16</Day>
</DateCompleted>
<DateRevised><Year>2016</Year>
<Month>11</Month>
<Day>25</Day>
</DateRevised>
<Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1460-2156</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>138</Volume>
<Issue>Pt 9</Issue>
<PubDate><Year>2015</Year>
<Month>Sep</Month>
</PubDate>
</JournalIssue>
<Title>Brain : a journal of neurology</Title>
<ISOAbbreviation>Brain</ISOAbbreviation>
</Journal>
<ArticleTitle>Glucocerebrosidase activity in Parkinson's disease with and without GBA mutations.</ArticleTitle>
<Pagination><MedlinePgn>2648-58</MedlinePgn>
</Pagination>
<ELocationID EIdType="doi" ValidYN="Y">10.1093/brain/awv179</ELocationID>
<Abstract><AbstractText>Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with idiopathic Parkinson's disease (after exclusion of all GBA and LRRK2 carriers; 11.53 µmol/l/h, versus 12.11 µmol/l/h, P = 0.036) and after adjustment for age and gender (P = 0.012). Interestingly, LRRK2 G2019S carriers (n = 36), most of whom had Parkinson's disease, had higher enzymatic activity than non-carriers (13.69 µmol/l/h versus 11.93 µmol/l/h, P = 0.002). In patients with idiopathic Parkinson's, higher glucocerebrosidase enzymatic activity was associated with longer disease duration (P = 0.002) in adjusted models, suggesting a milder disease course. We conclude that lower glucocerebrosidase enzymatic activity is strongly associated with GBA mutations, and modestly with idiopathic Parkinson's disease. The association of lower glucocerebrosidase activity in both GBA mutation carriers and Parkinson's patients without GBA mutations suggests that loss of glucocerebrosidase function contributes to the pathogenesis of Parkinson's disease. High glucocerebrosidase enzymatic activity in LRRK2 G2019S carriers may reflect a distinct pathogenic mechanism. Taken together, these data suggest that glucocerebrosidase enzymatic activity could be a modifiable therapeutic target.</AbstractText>
<CopyrightInformation>© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</CopyrightInformation>
</Abstract>
<AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Alcalay</LastName>
<ForeName>Roy N</ForeName>
<Initials>RN</Initials>
<AffiliationInfo><Affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA rna2104@columbia.edu.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Levy</LastName>
<ForeName>Oren A</ForeName>
<Initials>OA</Initials>
<AffiliationInfo><Affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Waters</LastName>
<ForeName>Cheryl C</ForeName>
<Initials>CC</Initials>
<AffiliationInfo><Affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Fahn</LastName>
<ForeName>Stanley</ForeName>
<Initials>S</Initials>
<AffiliationInfo><Affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Ford</LastName>
<ForeName>Blair</ForeName>
<Initials>B</Initials>
<AffiliationInfo><Affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Kuo</LastName>
<ForeName>Sheng-Han</ForeName>
<Initials>SH</Initials>
<AffiliationInfo><Affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Mazzoni</LastName>
<ForeName>Pietro</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Pauciulo</LastName>
<ForeName>Michael W</ForeName>
<Initials>MW</Initials>
<AffiliationInfo><Affiliation>3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics; University of Cincinnati College of Medicine, Cincinnati, OH, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Nichols</LastName>
<ForeName>William C</ForeName>
<Initials>WC</Initials>
<AffiliationInfo><Affiliation>3 Division of Human Genetics, Cincinnati Children's Hospital Medical Center and the Department of Pediatrics; University of Cincinnati College of Medicine, Cincinnati, OH, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Gan-Or</LastName>
<ForeName>Ziv</ForeName>
<Initials>Z</Initials>
<AffiliationInfo><Affiliation>4 Montréal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Rouleau</LastName>
<ForeName>Guy A</ForeName>
<Initials>GA</Initials>
<AffiliationInfo><Affiliation>4 Montréal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Chung</LastName>
<ForeName>Wendy K</ForeName>
<Initials>WK</Initials>
<AffiliationInfo><Affiliation>5 Department of Pediatrics and Medicine, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Wolf</LastName>
<ForeName>Pavlina</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Oliva</LastName>
<ForeName>Petra</ForeName>
<Initials>P</Initials>
<AffiliationInfo><Affiliation>6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Keutzer</LastName>
<ForeName>Joan</ForeName>
<Initials>J</Initials>
<AffiliationInfo><Affiliation>6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Marder</LastName>
<ForeName>Karen</ForeName>
<Initials>K</Initials>
<AffiliationInfo><Affiliation>1 Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 2 Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA 7 Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, USA.</Affiliation>
</AffiliationInfo>
</Author>
<Author ValidYN="Y"><LastName>Zhang</LastName>
<ForeName>Xiaokui</ForeName>
<Initials>X</Initials>
<AffiliationInfo><Affiliation>6 Global BioTherapeutics, Genzyme, a Sanofi company, Framingham, MA, USA.</Affiliation>
</AffiliationInfo>
</Author>
</AuthorList>
<Language>eng</Language>
<GrantList CompleteYN="Y"><Grant><GrantID>U01NS052592</GrantID>
<Acronym>NS</Acronym>
<Agency>NINDS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>K02 NS080915</GrantID>
<Acronym>NS</Acronym>
<Agency>NINDS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>K08NS083738</GrantID>
<Acronym>NS</Acronym>
<Agency>NINDS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>NS036630</GrantID>
<Acronym>NS</Acronym>
<Agency>NINDS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R56 NS036630</GrantID>
<Acronym>NS</Acronym>
<Agency>NINDS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>UL1 TR000040</GrantID>
<Acronym>TR</Acronym>
<Agency>NCATS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>UL1 RR024156</GrantID>
<Acronym>RR</Acronym>
<Agency>NCRR NIH HHS</Agency>
<Country>United States</Country>
</Grant>
<Grant><GrantID>R01 NS036630</GrantID>
<Acronym>NS</Acronym>
<Agency>NINDS NIH HHS</Agency>
<Country>United States</Country>
</Grant>
</GrantList>
<PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType>
<PublicationType UI="D052061">Research Support, N.I.H., Extramural</PublicationType>
<PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType>
</PublicationTypeList>
<ArticleDate DateType="Electronic"><Year>2015</Year>
<Month>06</Month>
<Day>27</Day>
</ArticleDate>
</Article>
<MedlineJournalInfo><Country>England</Country>
<MedlineTA>Brain</MedlineTA>
<NlmUniqueID>0372537</NlmUniqueID>
<ISSNLinking>0006-8950</ISSNLinking>
</MedlineJournalInfo>
<ChemicalList><Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="C495280">LRRK2 protein, human</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="D000071158">Leucine-Rich Repeat Serine-Threonine Protein Kinase-2</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 2.7.11.1</RegistryNumber>
<NameOfSubstance UI="D017346">Protein-Serine-Threonine Kinases</NameOfSubstance>
</Chemical>
<Chemical><RegistryNumber>EC 3.2.1.45</RegistryNumber>
<NameOfSubstance UI="D005962">Glucosylceramidase</NameOfSubstance>
</Chemical>
</ChemicalList>
<CitationSubset>AIM</CitationSubset>
<CitationSubset>IM</CitationSubset>
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