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Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations
Macroautophagy is a lysosomal degradative pathway essential for neuron survival. Here, we show that macroautophagy requires the Alzheimer's disease (AD)-related protein presenilin-1 (PS1). In PS1 null blastocysts, neurons from mice hypomorphic for PS1 or conditionally depleted of PS1, substrate...
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| Published in: | Cell 2010-06, Vol.141 (7), p.1146-1158 |
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| creator | Lee, Ju-Hyun Yu, W. Haung Kumar, Asok Lee, Sooyeon Mohan, Panaiyur S. Peterhoff, Corrinne M. Wolfe, Devin M. Martinez-Vicente, Marta Massey, Ashish C. Sovak, Guy Uchiyama, Yasuo Westaway, David Cuervo, Ana Maria Nixon, Ralph A. |
| description | Macroautophagy is a lysosomal degradative pathway essential for neuron survival. Here, we show that macroautophagy requires the Alzheimer's disease (AD)-related protein presenilin-1 (PS1). In PS1 null blastocysts, neurons from mice hypomorphic for PS1 or conditionally depleted of PS1, substrate proteolysis and autophagosome clearance during macroautophagy are prevented as a result of a selective impairment of autolysosome acidification and cathepsin activation. These deficits are caused by failed PS1-dependent targeting of the v-ATPase V0a1 subunit to lysosomes. N-glycosylation of the V0a1 subunit, essential for its efficient ER-to-lysosome delivery, requires the selective binding of PS1 holoprotein to the unglycosylated subunit and the Sec61alpha/oligosaccharyltransferase complex. PS1 mutations causing early-onset AD produce a similar lysosomal/autophagy phenotype in fibroblasts from AD patients. PS1 is therefore essential for v-ATPase targeting to lysosomes, lysosome acidification, and proteolysis during autophagy. Defective lysosomal proteolysis represents a basis for pathogenic protein accumulations and neuronal cell death in AD and suggests previously unidentified therapeutic targets.
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► Presenilin-1 (PS1) is essential for lysosomal acidification and protein degradation ► v-ATPase V0a1 subunit glycosylation and delivery to lysosomes requires PS1 ► PS1 mutations impair lysosomal acidification and protein turnover by autophagy ► Neurons in PS1-deficient mice have lysosomal acidification deficits |
| doi_str_mv | 10.1016/j.cell.2010.05.008 |
| format | article |
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► Presenilin-1 (PS1) is essential for lysosomal acidification and protein degradation ► v-ATPase V0a1 subunit glycosylation and delivery to lysosomes requires PS1 ► PS1 mutations impair lysosomal acidification and protein turnover by autophagy ► Neurons in PS1-deficient mice have lysosomal acidification deficits</description><identifier>ISSN: 0092-8674</identifier><identifier>EISSN: 1097-4172</identifier><identifier>DOI: 10.1016/j.cell.2010.05.008</identifier><identifier>PMID: 20541250</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Alzheimer Disease - metabolism ; Alzheimer Disease - pathology ; Animals ; Autophagy ; Blastocyst - metabolism ; Cell Line ; CELLBIO ; Gene Deletion ; Gene Knockout Techniques ; Glycosylation ; Humans ; HUMDISEASE ; Hydrolysis ; Lysosomes - metabolism ; Mice ; Mice, Knockout ; Neurons - metabolism ; Presenilin-1 - genetics ; Presenilin-1 - metabolism ; Proteins - metabolism ; Vacuolar Proton-Translocating ATPases - metabolism ; Vacuoles - metabolism</subject><ispartof>Cell, 2010-06, Vol.141 (7), p.1146-1158</ispartof><rights>2010 Elsevier Inc.</rights><rights>2010 Published by Elsevier Inc. 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c552t-e4d138614bbaf8dbe3339b4a5df758c7394414b20a858f3d1c02bd864974ad643</citedby><cites>FETCH-LOGICAL-c552t-e4d138614bbaf8dbe3339b4a5df758c7394414b20a858f3d1c02bd864974ad643</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20541250$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, Ju-Hyun</creatorcontrib><creatorcontrib>Yu, W. Haung</creatorcontrib><creatorcontrib>Kumar, Asok</creatorcontrib><creatorcontrib>Lee, Sooyeon</creatorcontrib><creatorcontrib>Mohan, Panaiyur S.</creatorcontrib><creatorcontrib>Peterhoff, Corrinne M.</creatorcontrib><creatorcontrib>Wolfe, Devin M.</creatorcontrib><creatorcontrib>Martinez-Vicente, Marta</creatorcontrib><creatorcontrib>Massey, Ashish C.</creatorcontrib><creatorcontrib>Sovak, Guy</creatorcontrib><creatorcontrib>Uchiyama, Yasuo</creatorcontrib><creatorcontrib>Westaway, David</creatorcontrib><creatorcontrib>Cuervo, Ana Maria</creatorcontrib><creatorcontrib>Nixon, Ralph A.</creatorcontrib><title>Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations</title><title>Cell</title><addtitle>Cell</addtitle><description>Macroautophagy is a lysosomal degradative pathway essential for neuron survival. Here, we show that macroautophagy requires the Alzheimer's disease (AD)-related protein presenilin-1 (PS1). In PS1 null blastocysts, neurons from mice hypomorphic for PS1 or conditionally depleted of PS1, substrate proteolysis and autophagosome clearance during macroautophagy are prevented as a result of a selective impairment of autolysosome acidification and cathepsin activation. These deficits are caused by failed PS1-dependent targeting of the v-ATPase V0a1 subunit to lysosomes. N-glycosylation of the V0a1 subunit, essential for its efficient ER-to-lysosome delivery, requires the selective binding of PS1 holoprotein to the unglycosylated subunit and the Sec61alpha/oligosaccharyltransferase complex. PS1 mutations causing early-onset AD produce a similar lysosomal/autophagy phenotype in fibroblasts from AD patients. PS1 is therefore essential for v-ATPase targeting to lysosomes, lysosome acidification, and proteolysis during autophagy. Defective lysosomal proteolysis represents a basis for pathogenic protein accumulations and neuronal cell death in AD and suggests previously unidentified therapeutic targets.
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► Presenilin-1 (PS1) is essential for lysosomal acidification and protein degradation ► v-ATPase V0a1 subunit glycosylation and delivery to lysosomes requires PS1 ► PS1 mutations impair lysosomal acidification and protein turnover by autophagy ► Neurons in PS1-deficient mice have lysosomal acidification deficits</description><subject>Alzheimer Disease - metabolism</subject><subject>Alzheimer Disease - pathology</subject><subject>Animals</subject><subject>Autophagy</subject><subject>Blastocyst - metabolism</subject><subject>Cell Line</subject><subject>CELLBIO</subject><subject>Gene Deletion</subject><subject>Gene Knockout Techniques</subject><subject>Glycosylation</subject><subject>Humans</subject><subject>HUMDISEASE</subject><subject>Hydrolysis</subject><subject>Lysosomes - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Neurons - metabolism</subject><subject>Presenilin-1 - genetics</subject><subject>Presenilin-1 - metabolism</subject><subject>Proteins - metabolism</subject><subject>Vacuolar Proton-Translocating ATPases - metabolism</subject><subject>Vacuoles - metabolism</subject><issn>0092-8674</issn><issn>1097-4172</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><recordid>eNp9kV9LHDEUxYO06Kr9Aj6UefNptkkmmT9QhEWtLWxRbPscMskdN0tmsiYZYfrpm2FV9KVPgXN_5-RyD0JnBC8JJuWX7VKBtUuKk4D5EuP6AC0IbqqckYp-QAuMG5rXZcWO0HEIW5wIzvkhOqKYM0I5XqB-PQUXXC9tduddBGenYEImB52txuh2G_kwZffwOBoPiYAAg7FmyMgeSeKVCX7cRdBZO2Ur-3cDpgef34OVs3j3i2Q_xyijcUM4RR87aQN8en5P0J9v178vv-fr25sfl6t1rjinMQemSVGXhLWt7GrdQlEUTcsk113Fa1UVDWNpSLGsed0VmihMW12XrKmY1CUrTtDFPnc3tj1oBUP00oqdN730k3DSiPeTwWzEg3sSRckqVtIUcP4c4N3jCCGK3oT52nIANwZRcZYuyFmZSLonlXcheOhefyFYzDWJrZiNYq5JYC5SCcn0-e1-r5aXXhLwdQ9AutKTAS-CMjAo0KkHFYV25n_5_wClLKWi</recordid><startdate>20100625</startdate><enddate>20100625</enddate><creator>Lee, Ju-Hyun</creator><creator>Yu, W. Haung</creator><creator>Kumar, Asok</creator><creator>Lee, Sooyeon</creator><creator>Mohan, Panaiyur S.</creator><creator>Peterhoff, Corrinne M.</creator><creator>Wolfe, Devin M.</creator><creator>Martinez-Vicente, Marta</creator><creator>Massey, Ashish C.</creator><creator>Sovak, Guy</creator><creator>Uchiyama, Yasuo</creator><creator>Westaway, David</creator><creator>Cuervo, Ana Maria</creator><creator>Nixon, Ralph A.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><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>7TK</scope><scope>5PM</scope></search><sort><creationdate>20100625</creationdate><title>Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations</title><author>Lee, Ju-Hyun ; Yu, W. Haung ; Kumar, Asok ; Lee, Sooyeon ; Mohan, Panaiyur S. ; Peterhoff, Corrinne M. ; Wolfe, Devin M. ; Martinez-Vicente, Marta ; Massey, Ashish C. ; Sovak, Guy ; Uchiyama, Yasuo ; Westaway, David ; Cuervo, Ana Maria ; Nixon, Ralph A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c552t-e4d138614bbaf8dbe3339b4a5df758c7394414b20a858f3d1c02bd864974ad643</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Alzheimer Disease - metabolism</topic><topic>Alzheimer Disease - pathology</topic><topic>Animals</topic><topic>Autophagy</topic><topic>Blastocyst - metabolism</topic><topic>Cell Line</topic><topic>CELLBIO</topic><topic>Gene Deletion</topic><topic>Gene Knockout Techniques</topic><topic>Glycosylation</topic><topic>Humans</topic><topic>HUMDISEASE</topic><topic>Hydrolysis</topic><topic>Lysosomes - metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Neurons - metabolism</topic><topic>Presenilin-1 - genetics</topic><topic>Presenilin-1 - metabolism</topic><topic>Proteins - metabolism</topic><topic>Vacuolar Proton-Translocating ATPases - metabolism</topic><topic>Vacuoles - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Ju-Hyun</creatorcontrib><creatorcontrib>Yu, W. Haung</creatorcontrib><creatorcontrib>Kumar, Asok</creatorcontrib><creatorcontrib>Lee, Sooyeon</creatorcontrib><creatorcontrib>Mohan, Panaiyur S.</creatorcontrib><creatorcontrib>Peterhoff, Corrinne M.</creatorcontrib><creatorcontrib>Wolfe, Devin M.</creatorcontrib><creatorcontrib>Martinez-Vicente, Marta</creatorcontrib><creatorcontrib>Massey, Ashish C.</creatorcontrib><creatorcontrib>Sovak, Guy</creatorcontrib><creatorcontrib>Uchiyama, Yasuo</creatorcontrib><creatorcontrib>Westaway, David</creatorcontrib><creatorcontrib>Cuervo, Ana Maria</creatorcontrib><creatorcontrib>Nixon, Ralph A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Ju-Hyun</au><au>Yu, W. Haung</au><au>Kumar, Asok</au><au>Lee, Sooyeon</au><au>Mohan, Panaiyur S.</au><au>Peterhoff, Corrinne M.</au><au>Wolfe, Devin M.</au><au>Martinez-Vicente, Marta</au><au>Massey, Ashish C.</au><au>Sovak, Guy</au><au>Uchiyama, Yasuo</au><au>Westaway, David</au><au>Cuervo, Ana Maria</au><au>Nixon, Ralph A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations</atitle><jtitle>Cell</jtitle><addtitle>Cell</addtitle><date>2010-06-25</date><risdate>2010</risdate><volume>141</volume><issue>7</issue><spage>1146</spage><epage>1158</epage><pages>1146-1158</pages><issn>0092-8674</issn><eissn>1097-4172</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>WH Yu’s current address is Taub institute, Columbia University, New York, NY 10032</notes><abstract>Macroautophagy is a lysosomal degradative pathway essential for neuron survival. Here, we show that macroautophagy requires the Alzheimer's disease (AD)-related protein presenilin-1 (PS1). In PS1 null blastocysts, neurons from mice hypomorphic for PS1 or conditionally depleted of PS1, substrate proteolysis and autophagosome clearance during macroautophagy are prevented as a result of a selective impairment of autolysosome acidification and cathepsin activation. These deficits are caused by failed PS1-dependent targeting of the v-ATPase V0a1 subunit to lysosomes. N-glycosylation of the V0a1 subunit, essential for its efficient ER-to-lysosome delivery, requires the selective binding of PS1 holoprotein to the unglycosylated subunit and the Sec61alpha/oligosaccharyltransferase complex. PS1 mutations causing early-onset AD produce a similar lysosomal/autophagy phenotype in fibroblasts from AD patients. PS1 is therefore essential for v-ATPase targeting to lysosomes, lysosome acidification, and proteolysis during autophagy. Defective lysosomal proteolysis represents a basis for pathogenic protein accumulations and neuronal cell death in AD and suggests previously unidentified therapeutic targets.
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► Presenilin-1 (PS1) is essential for lysosomal acidification and protein degradation ► v-ATPase V0a1 subunit glycosylation and delivery to lysosomes requires PS1 ► PS1 mutations impair lysosomal acidification and protein turnover by autophagy ► Neurons in PS1-deficient mice have lysosomal acidification deficits</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>20541250</pmid><doi>10.1016/j.cell.2010.05.008</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cell, 2010-06, Vol.141 (7), p.1146-1158 |
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| language | eng |
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| source | BACON - Elsevier - GLOBAL_SCIENCEDIRECT-OPENACCESS |
| subjects | Alzheimer Disease - metabolism Alzheimer Disease - pathology Animals Autophagy Blastocyst - metabolism Cell Line CELLBIO Gene Deletion Gene Knockout Techniques Glycosylation Humans HUMDISEASE Hydrolysis Lysosomes - metabolism Mice Mice, Knockout Neurons - metabolism Presenilin-1 - genetics Presenilin-1 - metabolism Proteins - metabolism Vacuolar Proton-Translocating ATPases - metabolism Vacuoles - metabolism |
| title | Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations |
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