Degradative Organelles Containing Mislocalized α- and β-Synuclein Proliferate in Presenilin-1 Null Neurons
Presenilin-1 null mutation (PS1 -/-) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic α- and β-synuclei...
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| Veröffentlicht in: | The Journal of cell biology 2004-05, Vol.165 (3), p.335-346 |
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| creator | Wilson, Christina A. Murphy, Diane D. Giasson, Benoit I. Zhang, Bin Trojanowski, John Q. Virginia M.-Y. Lee |
| description | Presenilin-1 null mutation (PS1 -/-) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic α- and β-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with significant increases in the levels of both synucleins. Stimulation of autophagy in control neurons produced a similar mislocalization of synucleins as genetic ablation of PS1. These effects were not the result of the loss of PS1 γ-secretase activity; however, dysregulation of calcium channels in PS1 -/- cells may be involved. Finally, colocalization of α-synuclein and degradative organelles was observed in brains from patients with the Lewy body variant of AD. Thus, aberrant accumulation of α- and β-synuclein in degradative organelles are novel features of PS1 -/- neurons, and similar events may promote the formation of α-synuclein inclusions associated with neurodegenerative diseases. |
| doi_str_mv | 10.1083/jcb.200403061 |
| format | Article |
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Lee</creator><creatorcontrib>Wilson, Christina A. ; Murphy, Diane D. ; Giasson, Benoit I. ; Zhang, Bin ; Trojanowski, John Q. ; Virginia M.-Y. Lee</creatorcontrib><description>Presenilin-1 null mutation (PS1 -/-) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic α- and β-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with significant increases in the levels of both synucleins. Stimulation of autophagy in control neurons produced a similar mislocalization of synucleins as genetic ablation of PS1. These effects were not the result of the loss of PS1 γ-secretase activity; however, dysregulation of calcium channels in PS1 -/- cells may be involved. Finally, colocalization of α-synuclein and degradative organelles was observed in brains from patients with the Lewy body variant of AD. Thus, aberrant accumulation of α- and β-synuclein in degradative organelles are novel features of PS1 -/- neurons, and similar events may promote the formation of α-synuclein inclusions associated with neurodegenerative diseases.</description><identifier>ISSN: 0021-9525</identifier><identifier>EISSN: 1540-8140</identifier><identifier>DOI: 10.1083/jcb.200403061</identifier><identifier>PMID: 15123735</identifier><identifier>CODEN: JCLBA3</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Aged ; Aged, 80 and over ; alpha-Synuclein ; Amyloid Precursor Protein Secretases ; Animals ; Antibodies ; Antigens, CD - metabolism ; Aspartic Acid Endopeptidases ; Autophagy - genetics ; beta-Synuclein ; Brain ; Brain - metabolism ; Brain - pathology ; Brain - physiopathology ; Calcium ; Calcium Channels - genetics ; Calcium Channels - metabolism ; Cells ; Cells, Cultured ; Cellular biology ; Disease ; Endopeptidases - metabolism ; Female ; Humans ; Inclusion Bodies - genetics ; Inclusion Bodies - metabolism ; Lysosomal Membrane Proteins ; Lysosomes - metabolism ; Lysosomes - pathology ; Lysosomes - ultrastructure ; Male ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Membrane Proteins - physiology ; Mice ; Mice, Knockout ; Microscopy, Electron ; Middle Aged ; Mutation - genetics ; Nerve Tissue Proteins - metabolism ; Neurodegenerative Diseases - genetics ; Neurodegenerative Diseases - metabolism ; Neurodegenerative Diseases - pathology ; Neurological disorders ; Neurons ; Neurons - metabolism ; Neurons - pathology ; Neuroscience ; Organelles ; Parkinson disease ; Presenilin-1 ; Presenilins ; Protein Transport - genetics ; Synucleins ; Up-Regulation - genetics ; Vacuoles - metabolism ; Vacuoles - pathology</subject><ispartof>The Journal of cell biology, 2004-05, Vol.165 (3), p.335-346</ispartof><rights>Copyright 2004 The Rockefeller University Press</rights><rights>Copyright the Rockefeller University Press</rights><rights>Copyright Rockefeller University Press May 10, 2004</rights><rights>Copyright © 2004, The Rockefeller University Press</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-9527c36a0e93f7880bf891696c7c3e311528463f7f96a14e864fb9897eff8f353</citedby><cites>FETCH-LOGICAL-c462t-9527c36a0e93f7880bf891696c7c3e311528463f7f96a14e864fb9897eff8f353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15123735$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wilson, Christina A.</creatorcontrib><creatorcontrib>Murphy, Diane D.</creatorcontrib><creatorcontrib>Giasson, Benoit I.</creatorcontrib><creatorcontrib>Zhang, Bin</creatorcontrib><creatorcontrib>Trojanowski, John Q.</creatorcontrib><creatorcontrib>Virginia M.-Y. Lee</creatorcontrib><title>Degradative Organelles Containing Mislocalized α- and β-Synuclein Proliferate in Presenilin-1 Null Neurons</title><title>The Journal of cell biology</title><addtitle>J Cell Biol</addtitle><description>Presenilin-1 null mutation (PS1 -/-) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic α- and β-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with significant increases in the levels of both synucleins. Stimulation of autophagy in control neurons produced a similar mislocalization of synucleins as genetic ablation of PS1. These effects were not the result of the loss of PS1 γ-secretase activity; however, dysregulation of calcium channels in PS1 -/- cells may be involved. Finally, colocalization of α-synuclein and degradative organelles was observed in brains from patients with the Lewy body variant of AD. Thus, aberrant accumulation of α- and β-synuclein in degradative organelles are novel features of PS1 -/- neurons, and similar events may promote the formation of α-synuclein inclusions associated with neurodegenerative diseases.</description><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>alpha-Synuclein</subject><subject>Amyloid Precursor Protein Secretases</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antigens, CD - metabolism</subject><subject>Aspartic Acid Endopeptidases</subject><subject>Autophagy - genetics</subject><subject>beta-Synuclein</subject><subject>Brain</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Brain - physiopathology</subject><subject>Calcium</subject><subject>Calcium Channels - genetics</subject><subject>Calcium Channels - metabolism</subject><subject>Cells</subject><subject>Cells, Cultured</subject><subject>Cellular biology</subject><subject>Disease</subject><subject>Endopeptidases - metabolism</subject><subject>Female</subject><subject>Humans</subject><subject>Inclusion Bodies - genetics</subject><subject>Inclusion Bodies - metabolism</subject><subject>Lysosomal Membrane Proteins</subject><subject>Lysosomes - metabolism</subject><subject>Lysosomes - pathology</subject><subject>Lysosomes - ultrastructure</subject><subject>Male</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Membrane Proteins - physiology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microscopy, Electron</subject><subject>Middle Aged</subject><subject>Mutation - genetics</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neurodegenerative Diseases - genetics</subject><subject>Neurodegenerative Diseases - metabolism</subject><subject>Neurodegenerative Diseases - pathology</subject><subject>Neurological disorders</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neuroscience</subject><subject>Organelles</subject><subject>Parkinson disease</subject><subject>Presenilin-1</subject><subject>Presenilins</subject><subject>Protein Transport - genetics</subject><subject>Synucleins</subject><subject>Up-Regulation - genetics</subject><subject>Vacuoles - metabolism</subject><subject>Vacuoles - pathology</subject><issn>0021-9525</issn><issn>1540-8140</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc-KFDEQxoMo7rh69CYSPHjrNZV0p9MXQca_sO4K6jlkMpUxQyZZk-6F9a30QXwm086wq16EQJHUj68q30fIQ2AnwJR4trWrE85YywSTcIssoGtZo6Blt8mCMQ7N0PHuiNwrZcsq1rfiLjmCDrjoRbcg4SVuslmb0V8iPc8bEzEELHSZ4mh89HFD3_sSkjXBf8M1_fm9oSbW-qP5eBUnG9BH-iGn4B1mMyL9fcWC0QcfG6BnUwj0DKecYrlP7jgTCj441GPy-fWrT8u3zen5m3fLF6eNbSUf5417K6RhOAjXK8VWTg0gB2nrMwqAjqtW1pYbpIEWlWzdalBDj84pJzpxTJ7vdS-m1Q7XFuOYTdAX2e9MvtLJeP13J_ovepMuNYe-HlUFnh4Ecvo6YRn1zhdbnan2pKnoHgbOAOC_IPSyG4DPik_-AbdpyrG6MA9lqgYy793sIZtTKRnd9crA9Jy2rmnr67Qr__jPf97Qh3gr8GgPbMuY8k1fcs4ZF78AdOKwYg</recordid><startdate>20040510</startdate><enddate>20040510</enddate><creator>Wilson, Christina A.</creator><creator>Murphy, Diane D.</creator><creator>Giasson, Benoit I.</creator><creator>Zhang, Bin</creator><creator>Trojanowski, John Q.</creator><creator>Virginia M.-Y. Lee</creator><general>Rockefeller University Press</general><general>The Rockefeller University Press</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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20040510</creationdate><title>Degradative Organelles Containing Mislocalized α- and β-Synuclein Proliferate in Presenilin-1 Null Neurons</title><author>Wilson, Christina A. ; Murphy, Diane D. ; Giasson, Benoit I. ; Zhang, Bin ; Trojanowski, John Q. ; Virginia M.-Y. Lee</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c462t-9527c36a0e93f7880bf891696c7c3e311528463f7f96a14e864fb9897eff8f353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>alpha-Synuclein</topic><topic>Amyloid Precursor Protein Secretases</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antigens, CD - metabolism</topic><topic>Aspartic Acid Endopeptidases</topic><topic>Autophagy - genetics</topic><topic>beta-Synuclein</topic><topic>Brain</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Brain - physiopathology</topic><topic>Calcium</topic><topic>Calcium Channels - genetics</topic><topic>Calcium Channels - metabolism</topic><topic>Cells</topic><topic>Cells, Cultured</topic><topic>Cellular biology</topic><topic>Disease</topic><topic>Endopeptidases - metabolism</topic><topic>Female</topic><topic>Humans</topic><topic>Inclusion Bodies - genetics</topic><topic>Inclusion Bodies - metabolism</topic><topic>Lysosomal Membrane Proteins</topic><topic>Lysosomes - metabolism</topic><topic>Lysosomes - pathology</topic><topic>Lysosomes - ultrastructure</topic><topic>Male</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Membrane Proteins - physiology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microscopy, Electron</topic><topic>Middle Aged</topic><topic>Mutation - genetics</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Neurodegenerative Diseases - genetics</topic><topic>Neurodegenerative Diseases - metabolism</topic><topic>Neurodegenerative Diseases - pathology</topic><topic>Neurological disorders</topic><topic>Neurons</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Neuroscience</topic><topic>Organelles</topic><topic>Parkinson disease</topic><topic>Presenilin-1</topic><topic>Presenilins</topic><topic>Protein Transport - genetics</topic><topic>Synucleins</topic><topic>Up-Regulation - genetics</topic><topic>Vacuoles - metabolism</topic><topic>Vacuoles - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wilson, Christina A.</creatorcontrib><creatorcontrib>Murphy, Diane D.</creatorcontrib><creatorcontrib>Giasson, Benoit I.</creatorcontrib><creatorcontrib>Zhang, Bin</creatorcontrib><creatorcontrib>Trojanowski, John Q.</creatorcontrib><creatorcontrib>Virginia M.-Y. 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Lee</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Degradative Organelles Containing Mislocalized α- and β-Synuclein Proliferate in Presenilin-1 Null Neurons</atitle><jtitle>The Journal of cell biology</jtitle><addtitle>J Cell Biol</addtitle><date>2004-05-10</date><risdate>2004</risdate><volume>165</volume><issue>3</issue><spage>335</spage><epage>346</epage><pages>335-346</pages><issn>0021-9525</issn><eissn>1540-8140</eissn><coden>JCLBA3</coden><abstract>Presenilin-1 null mutation (PS1 -/-) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic α- and β-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with significant increases in the levels of both synucleins. Stimulation of autophagy in control neurons produced a similar mislocalization of synucleins as genetic ablation of PS1. These effects were not the result of the loss of PS1 γ-secretase activity; however, dysregulation of calcium channels in PS1 -/- cells may be involved. Finally, colocalization of α-synuclein and degradative organelles was observed in brains from patients with the Lewy body variant of AD. Thus, aberrant accumulation of α- and β-synuclein in degradative organelles are novel features of PS1 -/- neurons, and similar events may promote the formation of α-synuclein inclusions associated with neurodegenerative diseases.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>15123735</pmid><doi>10.1083/jcb.200403061</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Aged, 80 and over alpha-Synuclein Amyloid Precursor Protein Secretases Animals Antibodies Antigens, CD - metabolism Aspartic Acid Endopeptidases Autophagy - genetics beta-Synuclein Brain Brain - metabolism Brain - pathology Brain - physiopathology Calcium Calcium Channels - genetics Calcium Channels - metabolism Cells Cells, Cultured Cellular biology Disease Endopeptidases - metabolism Female Humans Inclusion Bodies - genetics Inclusion Bodies - metabolism Lysosomal Membrane Proteins Lysosomes - metabolism Lysosomes - pathology Lysosomes - ultrastructure Male Membrane Proteins - genetics Membrane Proteins - metabolism Membrane Proteins - physiology Mice Mice, Knockout Microscopy, Electron Middle Aged Mutation - genetics Nerve Tissue Proteins - metabolism Neurodegenerative Diseases - genetics Neurodegenerative Diseases - metabolism Neurodegenerative Diseases - pathology Neurological disorders Neurons Neurons - metabolism Neurons - pathology Neuroscience Organelles Parkinson disease Presenilin-1 Presenilins Protein Transport - genetics Synucleins Up-Regulation - genetics Vacuoles - metabolism Vacuoles - pathology |
| title | Degradative Organelles Containing Mislocalized α- and β-Synuclein Proliferate in Presenilin-1 Null Neurons |
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