Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice
Publication Date
August 14, 2015
Journal
PLOS ONE
Authors
André R. A. Marques, Jan Aten, Roelof Ottenhoff, Cindy P. A. A. Van Roomen, et al
Volume
10
Issue
8
Pages
e0135889
DOI
https://dx.plos.org/10.1371/journal.pone.0135889
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0135889
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/26275242
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537125
Europe PMC
http://europepmc.org/abstract/MED/26275242
Web of Science
000359493600130
Scopus
84942894832
Mendeley
http://www.mendeley.com/research/reducing-gba2-activity-ameliorates-neuropathology-niemannpick-type-c-mice
Events
Loading … Spinner

Mendeley | Further Information

{"title"=>"Reducing GBA2 activity ameliorates neuropathology in niemann-pick type C mice", "type"=>"journal", "authors"=>[{"first_name"=>"André R.A.", "last_name"=>"Marques", "scopus_author_id"=>"55511811200"}, {"first_name"=>"Jan", "last_name"=>"Aten", "scopus_author_id"=>"17340122900"}, {"first_name"=>"Roelof", "last_name"=>"Ottenhoff", "scopus_author_id"=>"35496275700"}, {"first_name"=>"Cindy P.A.A.", "last_name"=>"Van Roomen", "scopus_author_id"=>"9233987000"}, {"first_name"=>"Daniela Herrera", "last_name"=>"Moro", "scopus_author_id"=>"56884150000"}, {"first_name"=>"Nike", "last_name"=>"Claessen", "scopus_author_id"=>"6602077013"}, {"first_name"=>"María Fernanda Vinueza", "last_name"=>"Veloz", "scopus_author_id"=>"56884529100"}, {"first_name"=>"Kuikui", "last_name"=>"Zhou", "scopus_author_id"=>"55355413900"}, {"first_name"=>"Zhanmin", "last_name"=>"Lin", "scopus_author_id"=>"56158490500"}, {"first_name"=>"Mina", "last_name"=>"Mirzaian", "scopus_author_id"=>"24169344900"}, {"first_name"=>"Rolf G.", "last_name"=>"Boot", "scopus_author_id"=>"56233828900"}, {"first_name"=>"Chris I.", "last_name"=>"De Zeeuw", "scopus_author_id"=>"35444285700"}, {"first_name"=>"Herman S.", "last_name"=>"Overkleeft", "scopus_author_id"=>"7005442878"}, {"first_name"=>"Yildiz", "last_name"=>"Yildiz", "scopus_author_id"=>"7004211531"}, {"first_name"=>"Johannes M.F.G.", "last_name"=>"Aerts", "scopus_author_id"=>"7102738034"}], "year"=>2015, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84942894832", "sgr"=>"84942894832", "doi"=>"10.1371/journal.pone.0135889", "pui"=>"606194828", "pmid"=>"26275242", "isbn"=>"1932-6203 (Electronic)\r1932-6203 (Linking)", "issn"=>"19326203"}, "id"=>"2a5b6cbb-3991-3dec-b310-663494c22841", "abstract"=>"The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2). Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1-/-) mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs), one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC.", "link"=>"http://www.mendeley.com/research/reducing-gba2-activity-ameliorates-neuropathology-niemannpick-type-c-mice", "reader_count"=>48, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>2, "Student > Master"=>6, "Other"=>3, "Student > Bachelor"=>8, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>10, "Student > Ph. D. Student"=>13, "Student > Postgraduate"=>2, "Student > Master"=>6, "Other"=>3, "Student > Bachelor"=>8, "Lecturer > Senior Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>11, "Agricultural and Biological Sciences"=>15, "Medicine and Dentistry"=>3, "Neuroscience"=>4, "Pharmacology, Toxicology and Pharmaceutical Science"=>1, "Sports and Recreations"=>1, "Chemistry"=>9, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Neuroscience"=>{"Neuroscience"=>4}, "Chemistry"=>{"Chemistry"=>9}, "Sports and Recreations"=>{"Sports and Recreations"=>1}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>11}, "Unspecified"=>{"Unspecified"=>3}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>1}}, "group_count"=>3}

Scopus | Further Information

{"@_fa"=>"true", "link"=>[{"@_fa"=>"true", "@ref"=>"self", "@href"=>"https://api.elsevier.com/content/abstract/scopus_id/84942894832"}, {"@_fa"=>"true", "@ref"=>"author-affiliation", "@href"=>"https://api.elsevier.com/content/abstract/scopus_id/84942894832?field=author,affiliation"}, {"@_fa"=>"true", "@ref"=>"scopus", "@href"=>"https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84942894832&origin=inward"}, {"@_fa"=>"true", "@ref"=>"scopus-citedby", "@href"=>"https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=84942894832&origin=inward"}], "prism:url"=>"https://api.elsevier.com/content/abstract/scopus_id/84942894832", "dc:identifier"=>"SCOPUS_ID:84942894832", "eid"=>"2-s2.0-84942894832", "dc:title"=>"Reducing GBA2 activity ameliorates neuropathology in niemann-pick type C mice", "dc:creator"=>"Marques A.", "prism:publicationName"=>"PLoS ONE", "prism:eIssn"=>"19326203", "prism:volume"=>"10", "prism:issueIdentifier"=>"8", "prism:pageRange"=>nil, "prism:coverDate"=>"2015-08-14", "prism:coverDisplayDate"=>"14 August 2015", "prism:doi"=>"10.1371/journal.pone.0135889", "citedby-count"=>"29", "affiliation"=>[{"@_fa"=>"true", "affilname"=>"Amsterdam UMC - University of Amsterdam", "affiliation-city"=>"Amsterdam", "affiliation-country"=>"Netherlands"}], "pubmed-id"=>"26275242", "prism:aggregationType"=>"Journal", "subtype"=>"ar", "subtypeDescription"=>"Article", "article-number"=>"e0135889", "source-id"=>"10600153309", "openaccess"=>"1", "openaccessFlag"=>true}

Facebook

  • {"url"=>"http%3A%2F%2Fjournals.plos.org%2Fplosone%2Farticle%3Fid%3D10.1371%252Fjournal.pone.0135889", "share_count"=>2, "like_count"=>0, "comment_count"=>1, "click_count"=>0, "total_count"=>3}

Counter

  • {"month"=>"8", "year"=>"2015", "pdf_views"=>"85", "xml_views"=>"5", "html_views"=>"279"}
  • {"month"=>"9", "year"=>"2015", "pdf_views"=>"40", "xml_views"=>"1", "html_views"=>"107"}
  • {"month"=>"10", "year"=>"2015", "pdf_views"=>"33", "xml_views"=>"1", "html_views"=>"75"}
  • {"month"=>"11", "year"=>"2015", "pdf_views"=>"12", "xml_views"=>"1", "html_views"=>"47"}
  • {"month"=>"12", "year"=>"2015", "pdf_views"=>"10", "xml_views"=>"0", "html_views"=>"53"}
  • {"month"=>"1", "year"=>"2016", "pdf_views"=>"17", "xml_views"=>"0", "html_views"=>"44"}
  • {"month"=>"2", "year"=>"2016", "pdf_views"=>"9", "xml_views"=>"0", "html_views"=>"39"}
  • {"month"=>"3", "year"=>"2016", "pdf_views"=>"13", "xml_views"=>"0", "html_views"=>"54"}
  • {"month"=>"4", "year"=>"2016", "pdf_views"=>"6", "xml_views"=>"0", "html_views"=>"24"}
  • {"month"=>"5", "year"=>"2016", "pdf_views"=>"17", "xml_views"=>"0", "html_views"=>"34"}
  • {"month"=>"6", "year"=>"2016", "pdf_views"=>"6", "xml_views"=>"0", "html_views"=>"38"}
  • {"month"=>"7", "year"=>"2016", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"17"}
  • {"month"=>"8", "year"=>"2016", "pdf_views"=>"9", "xml_views"=>"0", "html_views"=>"28"}
  • {"month"=>"9", "year"=>"2016", "pdf_views"=>"20", "xml_views"=>"0", "html_views"=>"47"}
  • {"month"=>"10", "year"=>"2016", "pdf_views"=>"10", "xml_views"=>"0", "html_views"=>"32"}
  • {"month"=>"11", "year"=>"2016", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"35"}
  • {"month"=>"12", "year"=>"2016", "pdf_views"=>"14", "xml_views"=>"0", "html_views"=>"30"}
  • {"month"=>"1", "year"=>"2017", "pdf_views"=>"24", "xml_views"=>"0", "html_views"=>"32"}
  • {"month"=>"2", "year"=>"2017", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"21"}
  • {"month"=>"3", "year"=>"2017", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"33"}
  • {"month"=>"4", "year"=>"2017", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"22"}
  • {"month"=>"5", "year"=>"2017", "pdf_views"=>"15", "xml_views"=>"0", "html_views"=>"50"}
  • {"month"=>"6", "year"=>"2017", "pdf_views"=>"10", "xml_views"=>"0", "html_views"=>"30"}
  • {"month"=>"7", "year"=>"2017", "pdf_views"=>"12", "xml_views"=>"1", "html_views"=>"34"}
  • {"month"=>"8", "year"=>"2017", "pdf_views"=>"10", "xml_views"=>"0", "html_views"=>"26"}
  • {"month"=>"9", "year"=>"2017", "pdf_views"=>"5", "xml_views"=>"0", "html_views"=>"19"}
  • {"month"=>"10", "year"=>"2017", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"48"}
  • {"month"=>"11", "year"=>"2017", "pdf_views"=>"7", "xml_views"=>"1", "html_views"=>"83"}
  • {"month"=>"12", "year"=>"2017", "pdf_views"=>"5", "xml_views"=>"1", "html_views"=>"105"}
  • {"month"=>"1", "year"=>"2018", "pdf_views"=>"8", "xml_views"=>"0", "html_views"=>"25"}
  • {"month"=>"2", "year"=>"2018", "pdf_views"=>"3", "xml_views"=>"0", "html_views"=>"19"}
  • {"month"=>"3", "year"=>"2018", "pdf_views"=>"13", "xml_views"=>"0", "html_views"=>"24"}
  • {"month"=>"4", "year"=>"2018", "pdf_views"=>"16", "xml_views"=>"1", "html_views"=>"27"}
  • {"month"=>"5", "year"=>"2018", "pdf_views"=>"10", "xml_views"=>"1", "html_views"=>"17"}
  • {"month"=>"6", "year"=>"2018", "pdf_views"=>"18", "xml_views"=>"0", "html_views"=>"14"}
  • {"month"=>"7", "year"=>"2018", "pdf_views"=>"10", "xml_views"=>"4", "html_views"=>"16"}
  • {"month"=>"8", "year"=>"2018", "pdf_views"=>"3", "xml_views"=>"3", "html_views"=>"7"}
  • {"month"=>"9", "year"=>"2018", "pdf_views"=>"17", "xml_views"=>"0", "html_views"=>"17"}
  • {"month"=>"10", "year"=>"2018", "pdf_views"=>"28", "xml_views"=>"1", "html_views"=>"15"}
  • {"month"=>"11", "year"=>"2018", "pdf_views"=>"4", "xml_views"=>"2", "html_views"=>"16"}
  • {"month"=>"12", "year"=>"2018", "pdf_views"=>"13", "xml_views"=>"2", "html_views"=>"9"}
  • {"month"=>"1", "year"=>"2019", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"17"}
  • {"month"=>"2", "year"=>"2019", "pdf_views"=>"7", "xml_views"=>"0", "html_views"=>"10"}
  • {"month"=>"3", "year"=>"2019", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"10"}
  • {"month"=>"4", "year"=>"2019", "pdf_views"=>"26", "xml_views"=>"3", "html_views"=>"21"}
  • {"month"=>"5", "year"=>"2019", "pdf_views"=>"17", "xml_views"=>"0", "html_views"=>"21"}
  • {"month"=>"6", "year"=>"2019", "pdf_views"=>"9", "xml_views"=>"0", "html_views"=>"24"}
  • {"month"=>"7", "year"=>"2019", "pdf_views"=>"4", "xml_views"=>"1", "html_views"=>"17"}
  • {"month"=>"8", "year"=>"2019", "pdf_views"=>"11", "xml_views"=>"0", "html_views"=>"13"}
  • {"month"=>"9", "year"=>"2019", "pdf_views"=>"3", "xml_views"=>"0", "html_views"=>"11"}
  • {"month"=>"10", "year"=>"2019", "pdf_views"=>"14", "xml_views"=>"0", "html_views"=>"18"}
  • {"month"=>"11", "year"=>"2019", "pdf_views"=>"18", "xml_views"=>"0", "html_views"=>"22"}
  • {"month"=>"12", "year"=>"2019", "pdf_views"=>"12", "xml_views"=>"1", "html_views"=>"9"}
  • {"month"=>"1", "year"=>"2020", "pdf_views"=>"22", "xml_views"=>"0", "html_views"=>"18"}

Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/2212752"], "description"=>"<p>(A) Survival Kaplan-Meier plot of transgenic mice resulting from the crossing of GBA2 deficiency into the <i>Npc1</i><sup><i>-/-</i></sup> background (<i>P logrank</i> = 0.0180 from <i>Npc1</i><sup><i>-/-</i></sup>/<i>Gba2</i><sup>+/+</sup>). (B) Maximal bodyweight, average lifespan, percentage lifespan increase and age at which bodyweight loss and neurological symptoms are patent in crossed animals. (C) Fluorescent labelling of GBA and GBA2 with ABP 1 (100 nM) and Western blotting with anti-GBA2 and anti-tubulin antibodies in brain homogenates of end-stage transgenic male mice. (D) GBA2 activity (assayed with 4MU-β-D-Glc substrate) in brain homogenates of end-stage transgenic mice relative to <i>Npc1</i><sup><i>+/+</i></sup>/<i>Gba2</i><sup>+/+</sup> (wt) values. (E) Sagittal cerebellar sections of end-stage transgenic mice immunostainned with anti-calbindin D-28K, -neurofilament and -GFAP antibodies. The arrows indicate calbindin D-28K positive cells (2<sup>nd</sup> panel from top) and swollen axons positive for neurofilament (3<sup>rd</sup> panel). Scale bar = 500 μm (top-panel) and 200 μm (other panels). (F) PC count in the anterior (A), central (C), posterior (P) and flocculonodular (N) transversal zones of the cerebellum of end-stage transgenic mice. Data (<i>n</i> = 5–6 per group, mean ± s.e.m.) were analyzed using the Kruskal-Wallis test with <i>post hoc</i> Dunn’s multiple comparison test.</p>", "links"=>[], "tags"=>["GBA 2 activity", "npc", "pc", "GBA 2", "Inhibiting GBA 2", "GBA 2 Activity Ameliorates Neuropathology"], "article_id"=>1511201, "categories"=>["Biological Sciences"], "users"=>["André R. A. Marques", "Jan Aten", "Roelof Ottenhoff", "Cindy P. A. A. van Roomen", "Daniela Herrera Moro", "Nike Claessen", "María Fernanda Vinueza Veloz", "Kuikui Zhou", "Zhanmin Lin", "Mina Mirzaian", "Rolf G. Boot", "Chris I. De Zeeuw", "Herman S. Overkleeft", "Yildiz Yildiz", "Johannes M. F. G. Aerts"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135889.g002", "stats"=>{"downloads"=>2, "page_views"=>25, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Crossing_of_Gba2__C57BL_6_129S6_SvEv_mice_with_Npc1__BALB_c_mice_/1511201", "title"=>"Crossing of <i>Gba2</i><sup><i>-/-</i></sup> (C57BL/6-129S6/SvEv) mice with <i>Npc1</i><sup><i>-/-</i></sup> (BALB/c) mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-14 02:58:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/2212755"], "description"=>"<p>(A) Kaplan-Meier survival plots of <i>Npc1</i><sup>-/-</sup> mice treated with 1 and 5 mg/kg.bw/day (mpk) of MZ-21 and MZ-31 (<i>P logrank</i> < 0.0001 from untreated <i>Npc1</i><sup>-/-</sup> mice). (B) Maximal bodyweight, average lifespan, percentage lifespan increase and age at which bodyweight loss and neurological symptoms are patent in <i>Npc1</i><sup><i>+/+</i></sup> and <i>Npc1</i><sup>-/-</sup> treated and untreated mice. (C) Fluorescent labelling of GBA and GBA2 with ABP 1 and immunostaining with anti-GBA2 and -tubulin antibodies in brain homogenates of <i>Npc1</i><sup><i>+/+</i></sup>, <i>Npc1</i><sup><i>+/-</i></sup> and <i>Npc1</i><sup>-/-</sup> treated and untreated 85- and 110-day-old mice. (D) GBA2 activity (assayed with 4MU-β-D-Glc substrate) in brain homogenates of <i>Npc1</i><sup><i>+/+</i></sup>, <i>Npc1</i><sup><i>+/-</i></sup> and <i>Npc1</i><sup>-/-</sup> treated and untreated 85-day-old mice relative to <i>Npc1</i><sup><i>+/+</i></sup> (wt) values. (E) Sagittal cerebellar sections of 85-days-old <i>Npc1</i><sup><i>+/+</i></sup> and <i>Npc1</i><sup><i>-/-</i></sup> treated and untreated immunostainned with antibodies against calbindin D-28K, neurofilament and GFAP. The arrows indicate calbindin D-28K positive cells (2<sup>nd</sup> panel from top) and swollen axons positive for neurofilament (3<sup>rd</sup> panel). Scale bar = 500 μm (top-panel) and 200 μm (other panels). (F) PC count in the anterior, central, posterior and flocculonodular areas of the cerebellum of <i>Npc1</i><sup>-/-</sup> treated and untreated 85-day-old mice. The line indicates <i>Npc1</i><sup>+/+</sup> levels. (G) Motor coordination of untreated and treated <i>Npc1</i><sup>-/-</sup> mice measured in the Erasmus Ladder. Step time (in ms) during perturbed sessions of <i>Npc1</i><sup><i>+/+</i></sup>, <i>Npc1</i><sup><i>+/-</i></sup><i>and Npc1</i><sup>-/-</sup> untreated (top) and treated (bottom) mice at six (session 5), nine (sessions 6 & 7) and ten (sessions 8 & 9) weeks of age. Data (<i>n</i> = 4–12 per group, mean ± s.e.m.) were analyzed using the Kruskal-Wallis test with <i>post hoc</i> Dunn’s multiple comparison test: * <i>P</i> < 0.05; ** <i>P</i> < 0.01; *** <i>P</i> < 0.001.</p>", "links"=>[], "tags"=>["GBA 2 activity", "npc", "pc", "GBA 2", "Inhibiting GBA 2", "GBA 2 Activity Ameliorates Neuropathology"], "article_id"=>1511204, "categories"=>["Biological Sciences"], "users"=>["André R. A. Marques", "Jan Aten", "Roelof Ottenhoff", "Cindy P. A. A. van Roomen", "Daniela Herrera Moro", "Nike Claessen", "María Fernanda Vinueza Veloz", "Kuikui Zhou", "Zhanmin Lin", "Mina Mirzaian", "Rolf G. Boot", "Chris I. De Zeeuw", "Herman S. Overkleeft", "Yildiz Yildiz", "Johannes M. F. G. Aerts"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135889.g003", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pharmacological_inhibition_of_GBA2_in_Npc1_BALB_c_mice_/1511204", "title"=>"Pharmacological inhibition of GBA2 in <i>Npc1</i><sup>-/-</sup> (BALB/c) mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-14 02:58:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/2212756"], "description"=>"<p>Levels of GalCer, GlcCer, Cer, GlcSph and gangliosides (GM3 and GM2), and activity of lysosomal enzymes β-hexosaminidase in whole brain homogenates of mice resulting from the crossing of <i>Gba2</i><sup>-/-</sup> mice with <i>Npc1</i><sup>-/-</sup> mice. Data (<i>n</i> = 5–6 per group) were analyzed using the Kruskal-Wallis test with <i>post hoc</i> Dunn’s multiple comparison test.</p><p>* <i>P</i> < 0.05,</p><p>** <i>P</i> < 0.01 and</p><p>*** <i>P</i> < 0.001 from <i>Npc1</i><sup>+/+</sup>/<i>Gba2</i><sup>+/+</sup></p><p>Genetic ablation of <i>Gba2</i> does not correct lysosomal defects.</p>", "links"=>[], "tags"=>["GBA 2 activity", "npc", "pc", "GBA 2", "Inhibiting GBA 2", "GBA 2 Activity Ameliorates Neuropathology"], "article_id"=>1511205, "categories"=>["Biological Sciences"], "users"=>["André R. A. Marques", "Jan Aten", "Roelof Ottenhoff", "Cindy P. A. A. van Roomen", "Daniela Herrera Moro", "Nike Claessen", "María Fernanda Vinueza Veloz", "Kuikui Zhou", "Zhanmin Lin", "Mina Mirzaian", "Rolf G. Boot", "Chris I. De Zeeuw", "Herman S. Overkleeft", "Yildiz Yildiz", "Johannes M. F. G. Aerts"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135889.t002", "stats"=>{"downloads"=>0, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genetic_ablation_of_Gba2_does_not_correct_lysosomal_defects_/1511205", "title"=>"Genetic ablation of <i>Gba2</i> does not correct lysosomal defects.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2015-08-14 02:58:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/2212749"], "description"=>"<p>(A) Chemical structures of ceramide (Cer), glucosylceramide (GlcCer), the ABP 1 specific for GBA and GBA2, and the inhibitors AMP-DNM (MZ-21) and <i>l</i>-ido-AMP-DNM (MZ-31) with respective IC<sub>50</sub> values. (B) Fluorescent labelling of GBA and GBA2 with ABP 1 and Western blotting with anti-GBA2, anti-GBA and anti-tubulin antibodies in brain homogenates of 85-day-old <i>Npc1</i><sup><i>+/+</i></sup>, <i>Npc1</i><sup><i>+/-</i></sup> and <i>Npc1</i><sup><i>-/-</i></sup> mice. (C) Ratio of GBA2 and GBA enzymatic activities (assayed with 4MU-β-D-Glc substrate) in brain homogenates of 85-day-old <i>Npc1</i><sup><i>+/+</i></sup>, <i>Npc1</i><sup><i>+/-</i></sup> and <i>Npc1</i><sup>-/-</sup> mice. (D) Fluorescent labelling of GBA and GBA2 with ABP 1 and Western blotting with anti-GBA2, anti-GBA and anti-tubulin antibodies in homogenates of dissected cerebella of 75-day-old <i>Npc1</i><sup><i>+/+</i></sup>, <i>Npc1</i><sup><i>+/-</i></sup> and <i>Npc1</i><sup><i>-/-</i></sup> mice. (E) Ratio of GBA2 and GBA enzymatic activities (assayed with 4MU-β-D-Glc substrate) in cerebellar homogenates of 75-day-old <i>Npc1</i><sup><i>+/+</i></sup>, <i>Npc1</i><sup><i>+/-</i></sup> and <i>Npc1</i><sup>-/-</sup> mice. (F) Fluorescent labelling of GBA2 with ABP 1 (top-right) in wild-type rat cerebellum by ICV injection. GBA was pre-blocked with conduritol-β-epoxide. Sections were also labelled with DAPI (top-left) and immunostained with anti-calbindin D-28K antibody (bottom-left). The arrow indicates a double-labelled cell. Scale bar = 50 μm. (G) Single immunostaining with anti-calbindin D-28K and anti-GBA2 antibodies (top) and double immunostaining with anti-GBA and anti-GBA2 antibodies (bottom) of cerebellar sagittal sections of 85-day-old <i>Npc1</i><sup>+/+</sup> and <i>Npc1</i><sup>-/-</sup> mice. The arrows indicate PC cell body (white) and dendrites (grey). Scale bars = 100 μm (top) and 50 μm (bottom).</p>", "links"=>[], "tags"=>["GBA 2 activity", "npc", "pc", "GBA 2", "Inhibiting GBA 2", "GBA 2 Activity Ameliorates Neuropathology"], "article_id"=>1511198, "categories"=>["Biological Sciences"], "users"=>["André R. A. Marques", "Jan Aten", "Roelof Ottenhoff", "Cindy P. A. A. van Roomen", "Daniela Herrera Moro", "Nike Claessen", "María Fernanda Vinueza Veloz", "Kuikui Zhou", "Zhanmin Lin", "Mina Mirzaian", "Rolf G. Boot", "Chris I. De Zeeuw", "Herman S. Overkleeft", "Yildiz Yildiz", "Johannes M. F. G. Aerts"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0135889.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_GBA_and_GBA2_in_brain_of_Npc1_and_Npc1_mice_/1511198", "title"=>"GBA and GBA2 in brain of <i>Npc1</i><sup>+/+</sup> and <i>Npc1</i><sup>-/-</sup> mice.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2015-08-14 02:58:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/2212776", "https://ndownloader.figshare.com/files/2212777", "https://ndownloader.figshare.com/files/2212778", "https://ndownloader.figshare.com/files/2212779", "https://ndownloader.figshare.com/files/2212780", "https://ndownloader.figshare.com/files/2212781", "https://ndownloader.figshare.com/files/2212782", "https://ndownloader.figshare.com/files/2212783", "https://ndownloader.figshare.com/files/2212784", "https://ndownloader.figshare.com/files/2212785", "https://ndownloader.figshare.com/files/2212786", "https://ndownloader.figshare.com/files/2212787"], "description"=>"<div><p>The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the <i>GBA</i> gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2). Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (<i>Npc1</i><sup>-/-</sup>) mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of <i>Npc1</i><sup>-/-</sup> mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs), one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in <i>Npc1</i><sup>-/-</sup> mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in <i>Npc1</i><sup>-/-</sup> mice. Our findings point to GBA2 activity as therapeutic target in NPC.</p></div>", "links"=>[], "tags"=>["GBA 2 activity", "npc", "pc", "GBA 2", "Inhibiting GBA 2", "GBA 2 Activity Ameliorates Neuropathology"], "article_id"=>1511217, "categories"=>["Biological Sciences"], "users"=>["André R. A. Marques", "Jan Aten", "Roelof Ottenhoff", "Cindy P. A. A. van Roomen", "Daniela Herrera Moro", "Nike Claessen", "María Fernanda Vinueza Veloz", "Kuikui Zhou", "Zhanmin Lin", "Mina Mirzaian", "Rolf G. Boot", "Chris I. De Zeeuw", "Herman S. Overkleeft", "Yildiz Yildiz", "Johannes M. F. G. Aerts"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0135889.s001", "https://dx.doi.org/10.1371/journal.pone.0135889.s002", "https://dx.doi.org/10.1371/journal.pone.0135889.s003", "https://dx.doi.org/10.1371/journal.pone.0135889.s004", "https://dx.doi.org/10.1371/journal.pone.0135889.s005", "https://dx.doi.org/10.1371/journal.pone.0135889.s006", "https://dx.doi.org/10.1371/journal.pone.0135889.s007", "https://dx.doi.org/10.1371/journal.pone.0135889.s008", "https://dx.doi.org/10.1371/journal.pone.0135889.s009", "https://dx.doi.org/10.1371/journal.pone.0135889.s010", "https://dx.doi.org/10.1371/journal.pone.0135889.s011", "https://dx.doi.org/10.1371/journal.pone.0135889.s012"], "stats"=>{"downloads"=>6, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Reducing_GBA2_Activity_Ameliorates_Neuropathology_in_Niemann_Pick_Type_C_Mice_/1511217", "title"=>"Reducing GBA2 Activity Ameliorates Neuropathology in Niemann-Pick Type C Mice", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2015-08-14 02:58:54"}

PMC Usage Stats | Further Information

  • {"unique-ip"=>"20", "full-text"=>"10", "pdf"=>"9", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"13", "supp-data"=>"11", "cited-by"=>"0", "year"=>"2015", "month"=>"8"}
  • {"unique-ip"=>"66", "full-text"=>"65", "pdf"=>"48", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"12", "supp-data"=>"28", "cited-by"=>"0", "year"=>"2015", "month"=>"9"}
  • {"unique-ip"=>"33", "full-text"=>"39", "pdf"=>"13", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"19", "supp-data"=>"14", "cited-by"=>"0", "year"=>"2015", "month"=>"10"}
  • {"unique-ip"=>"29", "full-text"=>"19", "pdf"=>"20", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"1"}
  • {"unique-ip"=>"20", "full-text"=>"19", "pdf"=>"15", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"2"}
  • {"unique-ip"=>"43", "full-text"=>"41", "pdf"=>"14", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"11"}
  • {"unique-ip"=>"25", "full-text"=>"21", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"11", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2015", "month"=>"12"}
  • {"unique-ip"=>"15", "full-text"=>"12", "pdf"=>"9", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"3"}
  • {"unique-ip"=>"19", "full-text"=>"20", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"4"}
  • {"unique-ip"=>"18", "full-text"=>"17", "pdf"=>"9", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"5"}
  • {"unique-ip"=>"25", "full-text"=>"27", "pdf"=>"12", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"9", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"6"}
  • {"unique-ip"=>"16", "full-text"=>"18", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2016", "month"=>"7"}
  • {"unique-ip"=>"18", "full-text"=>"16", "pdf"=>"7", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2016", "month"=>"8"}
  • {"unique-ip"=>"14", "full-text"=>"17", "pdf"=>"9", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"9"}
  • {"unique-ip"=>"15", "full-text"=>"14", "pdf"=>"8", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"8", "supp-data"=>"36", "cited-by"=>"1", "year"=>"2016", "month"=>"10"}
  • {"unique-ip"=>"15", "full-text"=>"14", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"11"}
  • {"unique-ip"=>"13", "full-text"=>"14", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2016", "month"=>"12"}
  • {"unique-ip"=>"10", "full-text"=>"8", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"5", "cited-by"=>"0", "year"=>"2017", "month"=>"1"}
  • {"unique-ip"=>"11", "full-text"=>"12", "pdf"=>"3", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"2"}
  • {"unique-ip"=>"14", "full-text"=>"13", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"3"}
  • {"unique-ip"=>"15", "full-text"=>"20", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"13", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"4"}
  • {"unique-ip"=>"9", "full-text"=>"7", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"5"}
  • {"unique-ip"=>"13", "full-text"=>"15", "pdf"=>"6", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2017", "month"=>"6"}
  • {"unique-ip"=>"9", "full-text"=>"10", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2017", "month"=>"7"}
  • {"unique-ip"=>"9", "full-text"=>"9", "pdf"=>"0", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2017", "month"=>"8"}
  • {"unique-ip"=>"13", "full-text"=>"13", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"9"}
  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"5", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"10"}
  • {"unique-ip"=>"12", "full-text"=>"12", "pdf"=>"2", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"7", "supp-data"=>"13", "cited-by"=>"3", "year"=>"2017", "month"=>"11"}
  • {"unique-ip"=>"8", "full-text"=>"7", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2017", "month"=>"12"}
  • {"unique-ip"=>"9", "full-text"=>"7", "pdf"=>"4", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"2", "supp-data"=>"4", "cited-by"=>"0", "year"=>"2018", "month"=>"1"}
  • {"unique-ip"=>"8", "full-text"=>"8", "pdf"=>"1", "abstract"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"3"}
  • {"unique-ip"=>"14", "full-text"=>"48", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"12", "cited-by"=>"3", "year"=>"2019", "month"=>"1"}
  • {"unique-ip"=>"12", "full-text"=>"14", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"11"}
  • {"unique-ip"=>"8", "full-text"=>"6", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"4"}
  • {"unique-ip"=>"15", "full-text"=>"13", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"12"}
  • {"unique-ip"=>"10", "full-text"=>"10", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"4", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"5"}
  • {"unique-ip"=>"22", "full-text"=>"17", "pdf"=>"5", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"6", "cited-by"=>"0", "year"=>"2018", "month"=>"6"}
  • {"unique-ip"=>"19", "full-text"=>"13", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"7", "cited-by"=>"0", "year"=>"2018", "month"=>"7"}
  • {"unique-ip"=>"9", "full-text"=>"7", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2018", "month"=>"8"}
  • {"unique-ip"=>"14", "full-text"=>"8", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2018", "month"=>"10"}
  • {"unique-ip"=>"4", "full-text"=>"5", "pdf"=>"1", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2018", "month"=>"9"}
  • {"unique-ip"=>"15", "full-text"=>"15", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"2"}
  • {"unique-ip"=>"11", "full-text"=>"9", "pdf"=>"7", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"3"}
  • {"unique-ip"=>"17", "full-text"=>"19", "pdf"=>"4", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"3", "supp-data"=>"2", "cited-by"=>"0", "year"=>"2019", "month"=>"4"}
  • {"unique-ip"=>"17", "full-text"=>"19", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"1", "supp-data"=>"1", "cited-by"=>"0", "year"=>"2019", "month"=>"5"}
  • {"unique-ip"=>"12", "full-text"=>"14", "pdf"=>"2", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"8"}
  • {"unique-ip"=>"13", "full-text"=>"13", "pdf"=>"3", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"5", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"9"}
  • {"unique-ip"=>"12", "full-text"=>"14", "pdf"=>"0", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"0", "cited-by"=>"0", "year"=>"2019", "month"=>"10"}
  • {"unique-ip"=>"13", "full-text"=>"10", "pdf"=>"6", "scanned-summary"=>"0", "scanned-page-browse"=>"0", "figure"=>"0", "supp-data"=>"7", "cited-by"=>"0", "year"=>"2019", "month"=>"12"}

Relative Metric

{"start_date"=>"2015-01-01T00:00:00Z", "end_date"=>"2015-12-31T00:00:00Z", "subject_areas"=>[]}
Loading … Spinner
There are currently no alerts