LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction
Identifieur interne : 002032 ( Ncbi/Merge ); précédent : 002031; suivant : 002033LRRK2 regulates retrograde synaptic compensation at the Drosophila neuromuscular junction
Auteurs : Jay Penney [Canada] ; Kazuya Tsurudome [Canada, États-Unis] ; Edward H. Liao [Canada, États-Unis] ; Grant Kauwe [États-Unis] ; Lindsay Gray [États-Unis] ; Akiko Yanagiya [Canada] ; Mario R. Calderon [Canada] ; Nahum Sonenberg [Canada] ; A. Pejmun Haghighi [Canada, États-Unis]Source :
- Nature Communications [ 2041-1723 ] ; 2016.
Abstract
Parkinson's disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes including the regulation of mitochondrial function, autophagy and endocytic dynamics; nevertheless, we know little about its potential role in the regulation of synaptic plasticity. Here we demonstrate that postsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensation at the larval neuromuscular junction. Conversely, postsynaptic overexpression of either the fly or human LRRK2 transgene induces a retrograde enhancement of presynaptic neurotransmitter release by increasing the size of the release ready pool of vesicles. We show that LRRK2 promotes cap-dependent translation and identify Furin 1 as its translational target, which is required for the synaptic function of LRRK2. As the regulation of synaptic homeostasis plays a fundamental role in ensuring normal and stable synaptic function, our findings suggest that aberrant function of LRRK2 may lead to destabilization of neural circuits.
Url:
DOI: 10.1038/ncomms12188
PubMed: 27432119
PubMed Central: 4960312
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Pejmun Haghighi</name><affiliation wicri:level="1"><nlm:aff id="a1"><institution>Department of Physiology, McGill University</institution>, 3655 Promenade Sir William Osler, Montreal, Quebec,<country>Canada</country> H3G 1Y6</nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="a2"><institution>Buck Institute for Research on Aging</institution>, 8001 Redwood Boulevard, Novato, California 94945,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Nature Communications</title><idno type="eISSN">2041-1723</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Parkinson's disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes including the regulation of mitochondrial function, autophagy and endocytic dynamics; nevertheless, we know little about its potential role in the regulation of synaptic plasticity. Here we demonstrate that postsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensation at the larval neuromuscular junction. Conversely, postsynaptic overexpression of either the fly or human LRRK2 transgene induces a retrograde enhancement of presynaptic neurotransmitter release by increasing the size of the release ready pool of vesicles. We show that LRRK2 promotes cap-dependent translation and identify Furin 1 as its translational target, which is required for the synaptic function of LRRK2. As the regulation of synaptic homeostasis plays a fundamental role in ensuring normal and stable synaptic function, our findings suggest that aberrant function of LRRK2 may lead to destabilization of neural circuits.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Davis, G W" uniqKey="Davis G">G. W. Davis</name></author><author><name sortKey="Muller, M" uniqKey="Muller M">M. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Nat Commun</journal-id><journal-id journal-id-type="iso-abbrev">Nat Commun</journal-id><journal-title-group><journal-title>Nature Communications</journal-title></journal-title-group><issn pub-type="epub">2041-1723</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">27432119</article-id><article-id pub-id-type="pmc">4960312</article-id><article-id pub-id-type="pii">ncomms12188</article-id><article-id pub-id-type="doi">10.1038/ncomms12188</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>LRRK2 regulates retrograde synaptic compensation at the <italic>Drosophila</italic> neuromuscular junction</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Penney</surname><given-names>Jay</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Tsurudome</surname><given-names>Kazuya</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Liao</surname><given-names>Edward H.</given-names></name><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Kauwe</surname><given-names>Grant</given-names></name><xref ref-type="aff" rid="a2">2</xref><xref ref-type="author-notes" rid="n1">*</xref></contrib><contrib contrib-type="author"><name><surname>Gray</surname><given-names>Lindsay</given-names></name><xref ref-type="aff" rid="a2">2</xref></contrib><contrib contrib-type="author"><name><surname>Yanagiya</surname><given-names>Akiko</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>R. Calderon</surname><given-names>Mario</given-names></name><xref ref-type="aff" rid="a1">1</xref></contrib><contrib contrib-type="author"><name><surname>Sonenberg</surname><given-names>Nahum</given-names></name><xref ref-type="aff" rid="a3">3</xref></contrib><contrib contrib-type="author"><name><surname>Haghighi</surname><given-names>A. Pejmun</given-names></name><xref ref-type="corresp" rid="c1">a</xref><xref ref-type="aff" rid="a1">1</xref><xref ref-type="aff" rid="a2">2</xref></contrib><aff id="a1"><label>1</label><institution>Department of Physiology, McGill University</institution>, 3655 Promenade Sir William Osler, Montreal, Quebec,<country>Canada</country> H3G 1Y6</aff><aff id="a2"><label>2</label><institution>Buck Institute for Research on Aging</institution>, 8001 Redwood Boulevard, Novato, California 94945,<country>USA</country></aff><aff id="a3"><label>3</label><institution>Department of Biochemistry, Goodman Cancer Research Centre, McGill University, McGill University</institution>, 1160 Pine Avenue West, Room 614, Montreal, Quebec,<country>Canada</country> H3A 1A3</aff></contrib-group><author-notes><corresp id="c1"><label>a</label><email>phaghighi@buckinstitute.org</email></corresp><fn id="n1"><label>*</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="epub"><day>19</day><month>07</month><year>2016</year></pub-date><pub-date pub-type="collection"><year>2016</year></pub-date><volume>7</volume><elocation-id>12188</elocation-id><history><date date-type="received"><day>18</day><month>11</month><year>2015</year></date><date date-type="accepted"><day>09</day><month>06</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link></license-p></license></permissions><abstract><p>Parkinson's disease gene leucine-rich repeat kinase 2 (LRRK2) has been implicated in a number of processes including the regulation of mitochondrial function, autophagy and endocytic dynamics; nevertheless, we know little about its potential role in the regulation of synaptic plasticity. Here we demonstrate that postsynaptic knockdown of the fly homologue of LRRK2 thwarts retrograde, homeostatic synaptic compensation at the larval neuromuscular junction. Conversely, postsynaptic overexpression of either the fly or human LRRK2 transgene induces a retrograde enhancement of presynaptic neurotransmitter release by increasing the size of the release ready pool of vesicles. We show that LRRK2 promotes cap-dependent translation and identify Furin 1 as its translational target, which is required for the synaptic function of LRRK2. As the regulation of synaptic homeostasis plays a fundamental role in ensuring normal and stable synaptic function, our findings suggest that aberrant function of LRRK2 may lead to destabilization of neural circuits.</p></abstract><abstract abstract-type="web-summary"><p><inline-graphic id="i1" xlink:href="ncomms12188-i1.jpg"></inline-graphic>Mutations in the protein LRRK2 have been associated with Parkinson's disease but little is still known about the basic functions of the protein in the brain. Here the authors show that in fruit flies, LRRK2 regulates retrograde homeostatic synaptic compensation at the larval neuromuscular junction.</p></abstract></article-meta></front><floats-group><fig id="f1"><label>Figure 1</label><caption><title>Postsynaptic dLRRK is required for homeostatic synaptic compensation at the <italic>Drosophila</italic> larval NMJ.</title><p>(<bold>a</bold>) Representative traces of mEJCs and EJCs from Control (<italic>MHC-Gal4</italic>/+), GluRIIA<sup>M/R</sup> OE (muscle overexpression of UAS<italic>-GluRIIA</italic><sup><italic>M/R</italic></sup>: UAS<italic>-GluRIIA</italic><sup><italic>M/R</italic></sup> /+; <italic>MHC-Gal4</italic>/+), GluRIIA<sup>M/R</sup> OE; <italic>dLrrk</italic> heterozygous mutants (UAS<italic>-GluRIIA</italic><sup><italic>M/R</italic></sup><italic>/+; MHC-Gal4/dLrrk</italic><sup><italic>e03680</italic></sup>). (<bold>b</bold>) Quantification of mEJC, EJC and QC from the genotypes shown in <bold>a</bold> and <italic>dLrrk</italic> heterozygotes. <italic>n</italic>=21, 27, 19 and 19. (<bold>c</bold>) Quantification of mEJC, EJC and QC from Control (<italic>w1118</italic>), <italic>GluRIIA</italic><sup><italic>−/−</italic></sup> (<italic>GluRIIA</italic><sup><italic>SP16</italic></sup>/<italic>Df(2L)cl-h4</italic>) and <italic>GluRIIA<sup>−/−</sup></italic>; <italic>dLrrk <sup>−/−</sup></italic> (<italic>GluRIIA</italic><sup><italic>SP16</italic></sup>/<italic>Df(2L)cl-h4</italic>; <italic>dLrrk</italic><sup><italic>e03680</italic></sup>), and representative EJC traces. <italic>n</italic>=32, 20 and 16. (<bold>d</bold>) Representative traces of mEJCs and EJCs from control (<italic>24B-Gal4</italic>/+), <italic>GluRIIA</italic> mutants carrying the 24B-Gal4 muscle driver (<italic>Df(2L)cl-h4/ GluRIIA</italic><sup><italic>SP16</italic></sup><italic>; 24B-Gal4/+</italic>) and <italic>GluRIIA</italic> mutants expressing <italic>dLrrk</italic>-RNAi in the muscle (<italic>Df(2L)cl-h4/ GluRIIA</italic><sup><italic>SP16</italic></sup><italic>; 24B-Gal4</italic>/UAS<italic>-dLRRK</italic>-RNAi). UAS-<italic>Dcr-2</italic> is also present in all combinations, except for control. (<bold>e</bold>) Quantification of mEJC, EJC and QC from the genotypes shown in <bold>d</bold> and in <italic>dLrrk</italic>-RNAi OE (UAS-<italic>Dcr-2</italic>/+; <italic>24B-Gal4</italic>/UAS-<italic>dLRRK</italic>-RNAi). <italic>n</italic>=19, 20, 18 and 19. (<bold>f</bold>) Quantification of mEJC, EJC and QC from BG380 (<italic>BG380-Gal4</italic>/+; <italic>+/GluRIIA</italic><sup><italic>SP16</italic></sup>), <italic>BG380; GluRIIA<sup>−/−</sup></italic> (<italic>BG380-Gal4</italic>/+; <italic>Df(2L)cl-h4/ GluRIIA</italic><sup><italic>SP16</italic></sup>) and <italic>BG380; GluRIIA<sup>−/−</sup></italic>; <italic>dLRRK</italic>-RNAi (<italic>BG380-Gal4</italic>/+; <italic>Df(2L)cl-h4/ GluRIIA</italic><sup><italic>SP16</italic></sup>; +/UAS-<italic>dLRRK</italic>-RNAi). UAS-<italic>Dcr-2</italic> is present in all combinations. <italic>n</italic>=17, 18 and 20. Error bars represent s.e.m. *<italic>P</italic><0.05, **<italic>P</italic><0.01 and ***<italic>P</italic><0.001. See <xref ref-type="supplementary-material" rid="S1">Supplementary Table 1</xref>.</p></caption><graphic xlink:href="ncomms12188-f1"></graphic></fig><fig id="f2"><label>Figure 2</label><caption><title>Postsynaptic overexpression of LRRK2 results in a retrograde enhancement in neurotransmitter release.</title><p>(<bold>a</bold>) Representative traces of mEJCs and EJCs from dLRRK control (UAS<italic>-dLRRK/+</italic>), muscle overexpression of dLRRK (<italic>G14-Gal4</italic>/UAS<italic>-dLRRK</italic>) and muscle overexpression of hLRRK2 (<italic>G14-Gal4</italic>/<italic>+</italic>; +/UAS<italic>-hLRRK2</italic>). EJCs are ten superimposed consecutive traces recorded at 0.5 Hz; mEJCs represent continuous recordings. For details of the number of recordings and statistics, see <xref ref-type="supplementary-material" rid="S1">Supplementary Table 1</xref>. (<bold>b</bold>) Quantification of mEJC, EJC and QC from the genotypes shown in <bold>a</bold> and control larvae for hLRRK2 overexpression (UAS<italic>-hLRRK2</italic>/+). <italic>n</italic>=21, 20, 20 and 28. (<bold>c</bold>) Quantification of EJCs at 0.5, 1.0, 1.5 and 3 mM external Ca<sup>2+</sup> concentrations for control (<italic>MHC-Gal4</italic>/+), <italic>n</italic>=20, 10, 12 and 13, and dLRRK OE (UAS-<italic>dLRRK/+; MHC-Gal4/+</italic>), <italic>n</italic>=20, 11, 13 and 15 NMJs. (<bold>d</bold>) Muscle 6/7 NMJs double-stained with anti-GluRIIC (red) and anti-HRP (blue) in control (<italic>MHC-Gal4</italic>/+) and larvae overexpressing dLRRK in the muscle (+/UAS<italic>-dLRRK</italic>; <italic>MHC-Gal4</italic>/+). Scale bar, 10 μm. (<bold>e</bold>) Quantification of total number of type 1 boutons and muscle surface area from the genotypes shown in <bold>d</bold> and larvae overexpressing hLRRK2 in muscle (<italic>MHC-Gal4</italic>/UAS<italic>-hLRRK2</italic>). <italic>n</italic>=10, 10 and 10 NMJs. (<bold>f</bold>) Quantification of mEJC, EJC and QC from MHC control (<italic>MHC-Gal4</italic>/+), dLRRK<sup>R1441C</sup> OE (UAS-dLRRK<sup>R1441C</sup>/+; <italic>MHC-Gal4</italic>/<italic>+</italic>) and dLRRK<sup>R1441G</sup> OE (<italic>MHC-Gal4</italic>/UAS<italic></italic>-dLRRK<sup>R1441G</sup>). <italic>n</italic>=15, 18 and 18. See also <xref ref-type="supplementary-material" rid="S1">Supplementary Table 1</xref>. (<bold>g</bold>) Quantification of mEJC, EJC and QC from MHC control (<italic>MHC-Gal4</italic>/<italic>+</italic>), hLRRK2 OE (<italic>MHC-Gal4</italic>/UAS-hLRRK2), hLRRK2<sup>I2020T</sup> OE (<italic>MHC-Gal4</italic>/UAS<italic></italic>-hLRRK2<sup>I2020T</sup>) and hLRRK2<sup>G2019S</sup> OE (<italic>MHC-Gal4</italic>/UAS<italic></italic>-hLRRK2<sup>G2019S</sup>). <italic>n</italic>=12, 13, 20 and 20. Error bars represent s.e.m. *<italic>P</italic><0.05, **<italic>P</italic><0.01 and ***<italic>P</italic><0.001. See also <xref ref-type="supplementary-material" rid="S1">Supplementary Table 1</xref>.</p></caption><graphic xlink:href="ncomms12188-f2"></graphic></fig><fig id="f3"><label>Figure 3</label><caption><title>Postsynaptic overexpression of dLRRK increases pool of readily releasable vesicles.</title><p>(<bold>a</bold>) Failure analysis of dLRRK OE larvae. Distribution of EJC amplitudes and mEJC amplitudes (inset) recorded under low external Ca<sup>2+</sup> concentrations (0.25 mM) for control (<italic>G14-Gal4</italic>/+, <italic>n</italic>=2,572 EJCs and 1,784 mEJCs (left), and larvae overexpressing dLRRK in the muscle (<italic>G14-Gal4</italic>/UAS<italic>-dLRRK</italic>, <italic>n</italic>=3,024 EJCs and 1,828 mEJCs) (middle). Black bars indicate events that were considered as failures. (control <italic>n</italic>=409, dLRRK OE <italic>n</italic>=152). Quantification of QC (right). **<italic>P</italic><0.001, Student's <italic>t</italic>-test. Error bars are s.e.m. (<bold>b</bold>) Representative (continuous recording) of EJC amplitudes in control (<italic>MHC-Gal4/+</italic>) larvae elicited at 0.2 Hz at the indicated Ca<sup>2+</sup> concentrations. (<bold>c</bold>) Representative parabolic variance–mean plots for control (<italic>MHC-Gal4</italic>/<italic>+</italic>) (solid) and overexpression of dLRRK (UAS<italic>-dLRRK</italic>/<italic>+</italic>; <italic>MHC-GAL4</italic>/<italic>+</italic>) in muscle (dotted). (<bold>d</bold>,<bold>e</bold>) Quantal parameters for the number of ready-release vesicles (<bold>d</bold>) and the probability of vesicle release (<bold>e</bold>) for overexpression of dLRRK (UAS<italic>-dLRRK</italic>/+; <italic>MHC-Gal4</italic>/+) and control (<italic>MHC-Gal4</italic>/+). <italic>n</italic>=7 and 5. (<bold>f</bold>,<bold>g</bold>) Mean cumulative EJC plot with back extrapolation of linear fit from the last ten stimuli to time zero (<bold>f</bold>) and bar graph shows the relative size of RRP (<bold>g</bold>) for overexpression of control (<italic>MHC-Gal4</italic>/+) and dLRRK OE (UAS-<italic>dLRRK/+; MHC-Gal4</italic>/+). <italic>n</italic>=8 and 10. Recordings performed in 3 mM Ca<sup>2+</sup> HL3 for 60 Hz, 30 stimuli. Error bars represent s.e.m. *<italic>P</italic><0.05 and **<italic>P</italic><0.01. See <xref ref-type="supplementary-material" rid="S1">Supplementary Table 1</xref>.</p></caption><graphic xlink:href="ncomms12188-f3"></graphic></fig><fig id="f4"><label>Figure 4</label><caption><title>Retrograde synaptic enhancement by dLRRK and hLRRK2 is dependent on translation.</title><p>(<bold>a</bold>) Representative traces of mEJCs and EJC from control (<italic>G14-Gal4</italic>/+), dLRRK muscle overexpression (<italic>G14-Gal4</italic>/UAS<italic>-dLRRK</italic>) and dLRRK muscle overexpression in <italic>eIF4E</italic> heterozygotes (<italic>G14-Gal4</italic>/UAS-<italic>dLRRK</italic>; <italic>eIF4E</italic><sup><italic>s058911</italic></sup>/+). (<bold>b</bold>) Quantification of mEJC, EJC and QC from the genotypes shown in <bold>a</bold>, as well as hLRRK2 overexpression in the muscle (+/<italic>G14-Gal4</italic>; UAS<italic>-hLRRK2</italic>/+) and hLRRK2 muscle overexpression in <italic>eIF4E</italic> heterozygotes (+/<italic>G14-Gal4</italic>; UAS<italic>-hLRRK2</italic>/<italic>eIF4E</italic><sup><italic>s058911</italic></sup>). <italic>n</italic>=13, 18, 16, 10 and 10. (<bold>c</bold>) Quantification of mEJC, EJC and QC from control larvae for dLRRK (UAS<italic>-dLRRK/+</italic>), larvae overexpressing dLRRK in muscle (<italic>G14-Gal4</italic>/UAS<italic>-dLRRK</italic>), dLRRK muscle overexpression in <italic>S6k</italic> heterozygotes (UAS<italic>-dLRRK</italic>/<italic>G14-Gal4</italic>; +/<italic>S6k</italic><sup><italic>l−1</italic></sup>), control larvae for hLRRK2 (UAS-<italic>hLRRK2</italic>/+), hLRRK2 overexpression in muscle (<italic>G14-Gal4</italic>/+; +/UAS-<italic>hLRRK2</italic>) and hLRRK2 muscle overexpression in <italic>S6k</italic> heterozygotes (+/G14-Gal4; UAS-<italic>hLRRK2</italic>/ <italic>S6k</italic><sup><italic>1−1</italic></sup>). <italic>n</italic>=21, 20, 20, 20, 28 and 20. (<bold>d</bold>) Quantification of mEJC, EJC and QC from larvae overexpressing dLRRK in muscle (<italic>MHC-Gal4</italic>/UAS<italic>-dLRRK</italic>) or in combination with <italic>Tor</italic> heterozygocity (UAS<italic>-dLRRK</italic>/<italic>MHC-Gal4</italic>; +/<italic>Tor). n</italic>=14 and 19. (<bold>e</bold>) Quantification of mEJC, EJC and QC from larvae overexpressing TOR in muscle (<italic>MHC-Gal4</italic>/UAS<italic>-TOR</italic>) or in combination with <italic>dLrrk</italic> heterozygocity (UAS<italic>-TOR</italic>/<italic>MHC-Gal4</italic>; +/<italic>dLrrk</italic><sup><italic>e03680</italic></sup><italic>). n</italic>=16 and 19. (<bold>f</bold>) Quantification of mEJC, EJC and QC from control larvae (<italic>MHC-Gal4</italic>/+) and larvae overexpressing dLRRK in muscle (+/UAS<italic>-dLRRK</italic>; <italic>MHC-Gal4</italic>/+) grown on normal food or food supplemented with 500 mg ml<sup>−1</sup> cycloheximide or 1 μM rapamycin for 12 h. <italic>n</italic>=10, 10, 10, 8 and 8. Error bars represent s.e.m. *<italic>P</italic><0.05, **<italic>P</italic><0.01 and ***<italic>P</italic><0.001. See also <xref ref-type="supplementary-material" rid="S1">Supplementary Table 1</xref>.</p></caption><graphic xlink:href="ncomms12188-f4"></graphic></fig><fig id="f5"><label>Figure 5</label><caption><title>dLRRK and hLRRK2 promote cap-dependent translation in postsynaptic muscles.</title><p>(<bold>a</bold>) Quantification of 5′-UTR luciferase reporter activity in response to co-transfection with either wild-type hLRRK2<sup>wt</sup> or kinase-dead hLRRK2<sup>3XKD</sup> normalized to psiCHECK2 response in HEK293T. <italic>n</italic>=3 experiments, *<italic>P</italic>=0.043. See also <xref ref-type="supplementary-material" rid="S1">Supplementary Table 2</xref>. (<bold>b</bold>) Western blot analysis of <italic>in vivo</italic> Fur1-5′-UTR-eGFP reporter expression when co-expressed with either dLRRK<sup>3KD</sup> (+/UAS-<italic>Fur1</italic>-5′-UTR-<italic>eGFP</italic>; UAS<italic>-dLRRK</italic><sup><italic>3KD</italic></sup>/<italic>MHC-Gal4</italic>) or wild-type dLRRK<sup>wt</sup> (UAS<italic>-dLRRK</italic><sup><italic>wt</italic></sup>/UAS-<italic>Fur1</italic>-5′-UTR-<italic>eGFP</italic>; +/<italic>MHC-Gal4</italic>). Left: Western blotting probed with (top) anti-GFP and (bottom) anti-Actin as loading control. Right: quantification of Fur1-5′-UTR-eGFP expression normalized to actin levels. <italic>n</italic>=3 for each. *<italic>P</italic><0.05. (<bold>c</bold>) Muscle 6 expression of Fur1-5′-UTR-eGFP in control (UAS-<italic>Fur1</italic>-5′-UTR-<italic>eGFP</italic>/<italic>24B-GAL4</italic>) and dLRRK-overexpressing larva (UAS<italic>-dLRRK</italic>/+; <italic>24B-GAL4</italic>/UAS-<italic>Fur1</italic>- 5′-UTR-<italic>eGFP</italic>). Scale bar, 100 μm. (<bold>d</bold>) Quantification of fluorescence intensity of muscles 6 and 7 normalized to muscle volume and expressed as a percentage of control. <italic>n</italic>=20 and 15 muscles, **<italic>P</italic>=0.001. (<bold>e</bold>) Muscle 4 NMJs stained with anti-Discs large (Dlg, red), anti-Fur1 (green) in control (<italic>MHC-Gal4</italic>/+) and dLRRK muscle overexpression larvae (+/UAS<italic>-dLRRK</italic>; <italic>MHC-Gal4</italic>/<italic>+</italic>). Scale bar, 10 μm. (<bold>f</bold>) Quantification of fluorescence intensity within Dlg area of genotypes in <bold>e</bold>. <italic>n</italic>=18 and 16 NMJs. *<italic>P</italic>=0.044. (<bold>g</bold>) Quantification of <italic>Fur1</italic> mRNA expression by qPCR. <italic>n</italic>=3 technical replicates. Error bars represent s.e.m. Student's <italic>t</italic>-test.</p></caption><graphic xlink:href="ncomms12188-f5"></graphic></fig><fig id="f6"><label>Figure 6</label><caption><title>Postsynaptic Fur1 is required for enhancement of synaptic transmission by dLRRK.</title><p>(<bold>a</bold>) Quantification of mEJC, EJC and QC from control (<italic>MHC-Gal4</italic>/<italic>+</italic>), dLRRK OE (UAS<italic>-dLRRK</italic>/<italic>+</italic>; <italic>MHC-Gal4</italic>/<italic>+</italic>) and dLRRK OE <italic>Fur1</italic>/+ (UAS<italic>-dLRRK</italic>/<italic>+</italic>; <italic>MHC-Gal4</italic>/<italic>Fur1</italic><sup><italic>rl205</italic></sup>). <italic>n</italic>=10, 10 and 10. (<bold>b</bold>) Representative traces for mEJC and EJC in control (<italic>MHC-Gal4/</italic>+), dLRRK and eGFP co-expression in muscle (<italic>+</italic>/UAS<italic>-dLRRK</italic>; <italic>MHC-Gal4</italic>/UAS<italic>-eGFP</italic>) and dLRRK muscle overexpression with <italic>Fur1</italic> RNAi (+/UAS<italic>-dLRRK</italic>; <italic>MHC-Gal4</italic>/UAS<italic>-Fur1-RNAi</italic>). (<bold>c</bold>) Quantification of mEJC, EJC and QC from the genotypes shown in <bold>a</bold>. <italic>n</italic>=18, 18 and 18. Error bars represent s.e.m. *<italic>P</italic><0.05, **<italic>P</italic><0.01 and ***<italic>P</italic><0.001. See also <xref ref-type="supplementary-material" rid="S1">Supplementary Table 1</xref>.</p></caption><graphic xlink:href="ncomms12188-f6"></graphic></fig><fig id="f7"><label>Figure 7</label><caption><title>hLRRK2<sup>G2019S</sup> inhibits retrograde signalling.</title><p>(<bold>a</bold>) Representative traces of mEJCs and EJC from larvae co-expressing dLRRK with hLRRK2<sup>wt</sup> (UAS-dLRRK/+; MHC-GAL4/UAS-hLRRK2<sup>wt</sup>) and larvae co-expressing dLRRK with hLRRK2<sup>G2019S</sup> (UAS-dLRRK/+; MHC-GAL4/UAS-hLRRK2<sup>G2019S</sup>). (<bold>b</bold>) Quantification of mEJC, EJC and QC from genotypes in <bold>a</bold> as well as control (MHC-Gal4/+). <italic>n</italic>=20, 20 and 22. (<bold>c</bold>) Representative traces of mEJCs and EJC from <italic>GluRIIA</italic> mutant larvae (<italic>Df(2L)cl-h4/GluRIIA</italic><sup><italic>SP16</italic></sup>) or <italic>GluRIIA</italic> mutant larvae expressing either wild-type or mutant hLRRK2 in muscle (<italic>Df(2L)cl-h4/GluRIIA</italic><sup><italic>SP16</italic></sup>; 24B-Gal4<italic>/</italic>UAS-hLRRK2<sup>wt</sup> and <italic>Df(2L)cl-h4/GluRIIA</italic><sup><italic>SP16</italic></sup>; 24B-Gal4<italic>/</italic>UAS-hLRRK2<sup>G2019S</sup>). (<bold>d</bold>) Quantification of mEJC, EJC and QC from <bold>c</bold>. <italic>n</italic>=20, 20 and 22. Error bars represent s.e.m. **<italic>P</italic><0.01 and ***<italic>P</italic><0.001.</p></caption><graphic xlink:href="ncomms12188-f7"></graphic></fig></floats-group></pmc><affiliations><list><country><li>Canada</li><li>États-Unis</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Penney, Jay" sort="Penney, Jay" uniqKey="Penney J" first="Jay" last="Penney">Jay Penney</name></noRegion><name sortKey="Haghighi, A Pejmun" sort="Haghighi, A Pejmun" uniqKey="Haghighi A" first="A. Pejmun" last="Haghighi">A. Pejmun Haghighi</name><name sortKey="Liao, Edward H" sort="Liao, Edward H" uniqKey="Liao E" first="Edward H." last="Liao">Edward H. Liao</name><name sortKey="R Calderon, Mario" sort="R Calderon, Mario" uniqKey="R Calderon M" first="Mario" last="R. Calderon">Mario R. Calderon</name><name sortKey="Sonenberg, Nahum" sort="Sonenberg, Nahum" uniqKey="Sonenberg N" first="Nahum" last="Sonenberg">Nahum Sonenberg</name><name sortKey="Tsurudome, Kazuya" sort="Tsurudome, Kazuya" uniqKey="Tsurudome K" first="Kazuya" last="Tsurudome">Kazuya Tsurudome</name><name sortKey="Yanagiya, Akiko" sort="Yanagiya, Akiko" uniqKey="Yanagiya A" first="Akiko" last="Yanagiya">Akiko Yanagiya</name></country><country name="États-Unis"><noRegion><name sortKey="Tsurudome, Kazuya" sort="Tsurudome, Kazuya" uniqKey="Tsurudome K" first="Kazuya" last="Tsurudome">Kazuya Tsurudome</name></noRegion><name sortKey="Gray, Lindsay" sort="Gray, Lindsay" uniqKey="Gray L" first="Lindsay" last="Gray">Lindsay Gray</name><name sortKey="Haghighi, A Pejmun" sort="Haghighi, A Pejmun" uniqKey="Haghighi A" first="A. Pejmun" last="Haghighi">A. Pejmun Haghighi</name><name sortKey="Kauwe, Grant" sort="Kauwe, Grant" uniqKey="Kauwe G" first="Grant" last="Kauwe">Grant Kauwe</name><name sortKey="Liao, Edward H" sort="Liao, Edward H" uniqKey="Liao E" first="Edward H." last="Liao">Edward H. Liao</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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