Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads invariably to fatal paralysis associated with motor neuron degeneration and muscular atrophy. One gene associated with ALS encodes the DNA/RNA-binding protein Fused in Sarcoma (FUS). There now exist two Drosop...
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Veröffentlicht in: | The Journal of neuroscience 2013-12, Vol.33 (50), p.19590-19598 |
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description | Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads invariably to fatal paralysis associated with motor neuron degeneration and muscular atrophy. One gene associated with ALS encodes the DNA/RNA-binding protein Fused in Sarcoma (FUS). There now exist two Drosophila models of ALS. In one, human FUS with ALS-causing mutations is expressed in fly motor neurons; in the other, the gene cabeza (caz), the fly homolog of FUS, is ablated. These FUS-ALS flies exhibit larval locomotor defects indicative of neuromuscular dysfunction and early death. The locus and site of initiation of this neuromuscular dysfunction remain unclear. We show here that in FUS-ALS flies, motor neuron cell bodies fire action potentials that propagate along the axon and voltage-dependent inward and outward currents in the cell bodies are indistinguishable in wild-type and FUS-ALS motor neurons. In marked contrast, the amplitude of synaptic currents evoked in the postsynaptic muscle cell is decreased by >80% in FUS-ALS larvae. Furthermore, the frequency but not unitary amplitude of spontaneous miniature synaptic currents is decreased dramatically in FUS-ALS flies, consistent with a change in quantal content but not quantal size. Although standard confocal microscopic analysis of the larval neuromuscular junction reveals no gross abnormalities, superresolution stimulated emission depletion (STED) microscopy demonstrates that the presynaptic active zone protein bruchpilot is aberrantly organized in FUS-ALS larvae. The results are consistent with the idea that defects in presynaptic terminal structure and function precede, and may contribute to, the later motor neuron degeneration that is characteristic of ALS. |
doi_str_mv | 10.1523/JNEUROSCI.3396-13.2013 |
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One gene associated with ALS encodes the DNA/RNA-binding protein Fused in Sarcoma (FUS). There now exist two Drosophila models of ALS. In one, human FUS with ALS-causing mutations is expressed in fly motor neurons; in the other, the gene cabeza (caz), the fly homolog of FUS, is ablated. These FUS-ALS flies exhibit larval locomotor defects indicative of neuromuscular dysfunction and early death. The locus and site of initiation of this neuromuscular dysfunction remain unclear. We show here that in FUS-ALS flies, motor neuron cell bodies fire action potentials that propagate along the axon and voltage-dependent inward and outward currents in the cell bodies are indistinguishable in wild-type and FUS-ALS motor neurons. In marked contrast, the amplitude of synaptic currents evoked in the postsynaptic muscle cell is decreased by >80% in FUS-ALS larvae. Furthermore, the frequency but not unitary amplitude of spontaneous miniature synaptic currents is decreased dramatically in FUS-ALS flies, consistent with a change in quantal content but not quantal size. Although standard confocal microscopic analysis of the larval neuromuscular junction reveals no gross abnormalities, superresolution stimulated emission depletion (STED) microscopy demonstrates that the presynaptic active zone protein bruchpilot is aberrantly organized in FUS-ALS larvae. The results are consistent with the idea that defects in presynaptic terminal structure and function precede, and may contribute to, the later motor neuron degeneration that is characteristic of ALS.</description><identifier>ISSN: 0270-6474</identifier><identifier>ISSN: 1529-2401</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.3396-13.2013</identifier><identifier>PMID: 24336723</identifier><language>eng</language><publisher>United States: Society for Neuroscience</publisher><subject>Amyotrophic Lateral Sclerosis - genetics ; Amyotrophic Lateral Sclerosis - metabolism ; Amyotrophic Lateral Sclerosis - pathology ; Animals ; Disease Models, Animal ; Drosophila ; Motor Neurons - metabolism ; Motor Neurons - pathology ; Nerve Degeneration - genetics ; Nerve Degeneration - metabolism ; Nerve Degeneration - pathology ; RNA-Binding Protein FUS - genetics ; RNA-Binding Protein FUS - metabolism ; Synapses - genetics ; Synapses - metabolism ; Synapses - pathology</subject><ispartof>The Journal of neuroscience, 2013-12, Vol.33 (50), p.19590-19598</ispartof><rights>Copyright © 2013 the authors 0270-6474/13/3319590-09$15.00/0 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c452t-774ac09c53ef063f99db0053cf2d5dc0ca424678445c9fad5300c4b10858a7c3</citedby><cites>FETCH-LOGICAL-c452t-774ac09c53ef063f99db0053cf2d5dc0ca424678445c9fad5300c4b10858a7c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858628/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858628/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24336723$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shahidullah, Mohammad</creatorcontrib><creatorcontrib>Le Marchand, Sylvain J</creatorcontrib><creatorcontrib>Fei, Hong</creatorcontrib><creatorcontrib>Zhang, Jiaming</creatorcontrib><creatorcontrib>Pandey, Udai Bhan</creatorcontrib><creatorcontrib>Dalva, Matthew B</creatorcontrib><creatorcontrib>Pasinelli, Piera</creatorcontrib><creatorcontrib>Levitan, Irwin B</creatorcontrib><title>Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads invariably to fatal paralysis associated with motor neuron degeneration and muscular atrophy. One gene associated with ALS encodes the DNA/RNA-binding protein Fused in Sarcoma (FUS). There now exist two Drosophila models of ALS. In one, human FUS with ALS-causing mutations is expressed in fly motor neurons; in the other, the gene cabeza (caz), the fly homolog of FUS, is ablated. These FUS-ALS flies exhibit larval locomotor defects indicative of neuromuscular dysfunction and early death. The locus and site of initiation of this neuromuscular dysfunction remain unclear. We show here that in FUS-ALS flies, motor neuron cell bodies fire action potentials that propagate along the axon and voltage-dependent inward and outward currents in the cell bodies are indistinguishable in wild-type and FUS-ALS motor neurons. In marked contrast, the amplitude of synaptic currents evoked in the postsynaptic muscle cell is decreased by >80% in FUS-ALS larvae. Furthermore, the frequency but not unitary amplitude of spontaneous miniature synaptic currents is decreased dramatically in FUS-ALS flies, consistent with a change in quantal content but not quantal size. Although standard confocal microscopic analysis of the larval neuromuscular junction reveals no gross abnormalities, superresolution stimulated emission depletion (STED) microscopy demonstrates that the presynaptic active zone protein bruchpilot is aberrantly organized in FUS-ALS larvae. The results are consistent with the idea that defects in presynaptic terminal structure and function precede, and may contribute to, the later motor neuron degeneration that is characteristic of ALS.</description><subject>Amyotrophic Lateral Sclerosis - genetics</subject><subject>Amyotrophic Lateral Sclerosis - metabolism</subject><subject>Amyotrophic Lateral Sclerosis - pathology</subject><subject>Animals</subject><subject>Disease Models, Animal</subject><subject>Drosophila</subject><subject>Motor Neurons - metabolism</subject><subject>Motor Neurons - pathology</subject><subject>Nerve Degeneration - genetics</subject><subject>Nerve Degeneration - metabolism</subject><subject>Nerve Degeneration - pathology</subject><subject>RNA-Binding Protein FUS - genetics</subject><subject>RNA-Binding Protein FUS - metabolism</subject><subject>Synapses - genetics</subject><subject>Synapses - metabolism</subject><subject>Synapses - pathology</subject><issn>0270-6474</issn><issn>1529-2401</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1vEzEQhi0EomngL1Q-ctnUn-vdC1KVtlAUUYm0Z8uxx-2ijb3YXqT-exxaIjhxGsnzzqMZPwidUbKikvHzL1-v7r_dbtc3K877tqF8xQjlr9CidvuGCUJfowVhijStUOIEneb8nRCiCFVv0QkTnLeK8QXKl-DBloyHgPNTMFMGnEuabZkTYBMc9nOwZYgBTwksOMD7WGLCAeZUHx08QIBkficq4zLFHKfHYTQ152DMOHp8fb9tEoymgMMXm-079MabMcP7l7pEd9dXd-vPzeb20836YtNYIVlplBLGkt5KDp603Pe92xEiufXMSWeJNYKJVnVCSNt74yQnxIodJZ3sjLJ8iT4-Y6d5twdnIZRkRj2lYW_Sk45m0P92wvCoH-JPzSugZV0FfHgBpPhjhlz0fsgWxtEEiHPWVEraMiqo-H9UKCVlp-odS9Q-R239qpzAHzeiRB_c6qNbfXCrKdcHt3Xw7O97jmN_ZPJf9xWi9g</recordid><startdate>20131211</startdate><enddate>20131211</enddate><creator>Shahidullah, Mohammad</creator><creator>Le Marchand, Sylvain J</creator><creator>Fei, Hong</creator><creator>Zhang, Jiaming</creator><creator>Pandey, Udai Bhan</creator><creator>Dalva, Matthew B</creator><creator>Pasinelli, Piera</creator><creator>Levitan, Irwin B</creator><general>Society for Neuroscience</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7SS</scope><scope>7TK</scope><scope>5PM</scope></search><sort><creationdate>20131211</creationdate><title>Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS</title><author>Shahidullah, Mohammad ; Le Marchand, Sylvain J ; Fei, Hong ; Zhang, Jiaming ; Pandey, Udai Bhan ; Dalva, Matthew B ; Pasinelli, Piera ; Levitan, Irwin B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c452t-774ac09c53ef063f99db0053cf2d5dc0ca424678445c9fad5300c4b10858a7c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amyotrophic Lateral Sclerosis - genetics</topic><topic>Amyotrophic Lateral Sclerosis - metabolism</topic><topic>Amyotrophic Lateral Sclerosis - pathology</topic><topic>Animals</topic><topic>Disease Models, Animal</topic><topic>Drosophila</topic><topic>Motor Neurons - metabolism</topic><topic>Motor Neurons - pathology</topic><topic>Nerve Degeneration - genetics</topic><topic>Nerve Degeneration - metabolism</topic><topic>Nerve Degeneration - pathology</topic><topic>RNA-Binding Protein FUS - genetics</topic><topic>RNA-Binding Protein FUS - metabolism</topic><topic>Synapses - genetics</topic><topic>Synapses - metabolism</topic><topic>Synapses - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shahidullah, Mohammad</creatorcontrib><creatorcontrib>Le Marchand, Sylvain J</creatorcontrib><creatorcontrib>Fei, Hong</creatorcontrib><creatorcontrib>Zhang, Jiaming</creatorcontrib><creatorcontrib>Pandey, Udai Bhan</creatorcontrib><creatorcontrib>Dalva, Matthew B</creatorcontrib><creatorcontrib>Pasinelli, Piera</creatorcontrib><creatorcontrib>Levitan, Irwin B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shahidullah, Mohammad</au><au>Le Marchand, Sylvain J</au><au>Fei, Hong</au><au>Zhang, Jiaming</au><au>Pandey, Udai Bhan</au><au>Dalva, Matthew B</au><au>Pasinelli, Piera</au><au>Levitan, Irwin B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2013-12-11</date><risdate>2013</risdate><volume>33</volume><issue>50</issue><spage>19590</spage><epage>19598</epage><pages>19590-19598</pages><issn>0270-6474</issn><issn>1529-2401</issn><eissn>1529-2401</eissn><abstract>Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease that leads invariably to fatal paralysis associated with motor neuron degeneration and muscular atrophy. One gene associated with ALS encodes the DNA/RNA-binding protein Fused in Sarcoma (FUS). There now exist two Drosophila models of ALS. In one, human FUS with ALS-causing mutations is expressed in fly motor neurons; in the other, the gene cabeza (caz), the fly homolog of FUS, is ablated. These FUS-ALS flies exhibit larval locomotor defects indicative of neuromuscular dysfunction and early death. The locus and site of initiation of this neuromuscular dysfunction remain unclear. We show here that in FUS-ALS flies, motor neuron cell bodies fire action potentials that propagate along the axon and voltage-dependent inward and outward currents in the cell bodies are indistinguishable in wild-type and FUS-ALS motor neurons. In marked contrast, the amplitude of synaptic currents evoked in the postsynaptic muscle cell is decreased by >80% in FUS-ALS larvae. Furthermore, the frequency but not unitary amplitude of spontaneous miniature synaptic currents is decreased dramatically in FUS-ALS flies, consistent with a change in quantal content but not quantal size. Although standard confocal microscopic analysis of the larval neuromuscular junction reveals no gross abnormalities, superresolution stimulated emission depletion (STED) microscopy demonstrates that the presynaptic active zone protein bruchpilot is aberrantly organized in FUS-ALS larvae. The results are consistent with the idea that defects in presynaptic terminal structure and function precede, and may contribute to, the later motor neuron degeneration that is characteristic of ALS.</abstract><cop>United States</cop><pub>Society for Neuroscience</pub><pmid>24336723</pmid><doi>10.1523/JNEUROSCI.3396-13.2013</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Amyotrophic Lateral Sclerosis - genetics Amyotrophic Lateral Sclerosis - metabolism Amyotrophic Lateral Sclerosis - pathology Animals Disease Models, Animal Drosophila Motor Neurons - metabolism Motor Neurons - pathology Nerve Degeneration - genetics Nerve Degeneration - metabolism Nerve Degeneration - pathology RNA-Binding Protein FUS - genetics RNA-Binding Protein FUS - metabolism Synapses - genetics Synapses - metabolism Synapses - pathology |
title | Defects in synapse structure and function precede motor neuron degeneration in Drosophila models of FUS-related ALS |
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