Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder
Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal...
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| Veröffentlicht in: | PloS one 2012-10, Vol.7 (10), p.e48273-e48273 |
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| description | Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1(-/-) mice relative to Npc1(+/-) at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher's disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1(-/-) as well as Balb/c Npc1(nmf164) mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1(-/-) mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1(-/-) spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation. |
| doi_str_mv | 10.1371/journal.pone.0048273 |
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Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1(-/-) mice relative to Npc1(+/-) at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher's disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1(-/-) as well as Balb/c Npc1(nmf164) mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1(-/-) mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1(-/-) spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0048273</identifier><identifier>PMID: 23094108</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Age ; Aging - genetics ; Aging - immunology ; Aging - pathology ; Analysis ; Animal models ; Animals ; Bacteria ; Bacterial diseases ; Biology ; Biomarkers ; Biomarkers - blood ; Brain ; Brain - immunology ; Brain - metabolism ; Care and treatment ; Cholesterol ; Damage detection ; Diagnosis ; Diagnostic systems ; Disease ; Disease Progression ; Female ; Gaucher's disease ; Gene Expression ; Gene regulation ; Genes ; Genetic engineering ; Genomes ; Humans ; Immunity ; Immunity (Disease) ; Immunity, Innate ; Immunohistochemistry ; Infections ; Innate immunity ; Intracellular Signaling Peptides and Proteins ; Leukocytes (neutrophilic) ; Liver ; Liver - immunology ; Liver - metabolism ; Liver diseases ; Lysosomes ; Lysosomes - genetics ; Lysosomes - immunology ; Lysosomes - metabolism ; Lysozyme ; Male ; Markers ; Medicine ; Mice ; Mice, Knockout ; Muramidase - blood ; Muramidase - genetics ; Mutants ; Mutation ; Neurodegeneration ; Neurological diseases ; Neutrophil Infiltration ; Neutrophils ; Neutrophils - immunology ; Neutrophils - metabolism ; Niemann-Pick disease ; Niemann-Pick Disease, Type C - genetics ; Niemann-Pick Disease, Type C - immunology ; Niemann-Pick Disease, Type C - pathology ; Npc1 protein ; Organs ; Pathophysiology ; Plasma ; Point mutation ; Proteins ; Proteins - genetics ; Proteins - immunology ; Proteins - metabolism ; Salmonella ; Spleen ; Spleen - immunology ; Spleen - metabolism ; Storage ; Tumor necrosis factor-TNF</subject><ispartof>PloS one, 2012-10, Vol.7 (10), p.e48273-e48273</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-a53737f8adfa9b3a9f62edf4109b1b699b6e2ef295501bf9026bb7fd18c933c93</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477142/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477142/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2919,23857,27915,27916,53782,53784,79361,79362</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23094108$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Barsh, Gregory S.</contributor><creatorcontrib>Alam, Md Suhail</creatorcontrib><creatorcontrib>Getz, Michelle</creatorcontrib><creatorcontrib>Safeukui, Innocent</creatorcontrib><creatorcontrib>Yi, Sue</creatorcontrib><creatorcontrib>Tamez, Pamela</creatorcontrib><creatorcontrib>Shin, Jenny</creatorcontrib><creatorcontrib>Velázquez, Peter</creatorcontrib><creatorcontrib>Haldar, Kasturi</creatorcontrib><title>Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1(-/-) mice relative to Npc1(+/-) at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher's disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1(-/-) as well as Balb/c Npc1(nmf164) mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1(-/-) mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1(-/-) spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation.</description><subject>Age</subject><subject>Aging - genetics</subject><subject>Aging - immunology</subject><subject>Aging - pathology</subject><subject>Analysis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Bacteria</subject><subject>Bacterial diseases</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Biomarkers - blood</subject><subject>Brain</subject><subject>Brain - immunology</subject><subject>Brain - metabolism</subject><subject>Care and treatment</subject><subject>Cholesterol</subject><subject>Damage detection</subject><subject>Diagnosis</subject><subject>Diagnostic systems</subject><subject>Disease</subject><subject>Disease Progression</subject><subject>Female</subject><subject>Gaucher's disease</subject><subject>Gene Expression</subject><subject>Gene regulation</subject><subject>Genes</subject><subject>Genetic engineering</subject><subject>Genomes</subject><subject>Humans</subject><subject>Immunity</subject><subject>Immunity (Disease)</subject><subject>Immunity, Innate</subject><subject>Immunohistochemistry</subject><subject>Infections</subject><subject>Innate immunity</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Leukocytes (neutrophilic)</subject><subject>Liver</subject><subject>Liver - immunology</subject><subject>Liver - metabolism</subject><subject>Liver diseases</subject><subject>Lysosomes</subject><subject>Lysosomes - genetics</subject><subject>Lysosomes - immunology</subject><subject>Lysosomes - metabolism</subject><subject>Lysozyme</subject><subject>Male</subject><subject>Markers</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Muramidase - blood</subject><subject>Muramidase - genetics</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Neurodegeneration</subject><subject>Neurological diseases</subject><subject>Neutrophil Infiltration</subject><subject>Neutrophils</subject><subject>Neutrophils - immunology</subject><subject>Neutrophils - metabolism</subject><subject>Niemann-Pick disease</subject><subject>Niemann-Pick Disease, Type C - genetics</subject><subject>Niemann-Pick Disease, Type C - immunology</subject><subject>Niemann-Pick Disease, Type C - pathology</subject><subject>Npc1 protein</subject><subject>Organs</subject><subject>Pathophysiology</subject><subject>Plasma</subject><subject>Point mutation</subject><subject>Proteins</subject><subject>Proteins - genetics</subject><subject>Proteins - immunology</subject><subject>Proteins - metabolism</subject><subject>Salmonella</subject><subject>Spleen</subject><subject>Spleen - immunology</subject><subject>Spleen - metabolism</subject><subject>Storage</subject><subject>Tumor necrosis factor-TNF</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk21r2zAQx83YWLtu32BsgsHYoMn04NjWm0EpW1coFPb0VpztU6JgS6nOLs2X2GeesqZdMvpiGGFb-v3_0p3usuyl4FOhSvFhGcbooZuugscp53klS_UoOxRayUkhuXq8832QPSNacj5TVVE8zQ6k4joXvDrMfp2hD71rGN6sIhK54Bkk2zUhsYjXCB1LP4FCD90xc97DgMz1_ejdsGarGAZ0no4ZEGsdIRCyJsSIXeIo8awfo_PI-tBiRyxYBn8NGQ0hwhw30hBbjM-zJxY6whfb91H24_On76dfJheXZ-enJxeTptBymMBMlaq0FbQWdK1A20Jia1NIuhZ1oXVdoEQr9WzGRW01l0Vdl7YVVaOVSuMoe33ru-oCmW0qyQgli1kh8nxDnN8SbYClWUXXQ1ybAM78mQhxbiAOrunQNGiVRKh1KZu8gboGzIWqMNeS21xVyevjdrex7rFt0A8Ruj3T_RXvFmYero3Ky1LkMhm82xrEcDUiDaZ31GDXgccwpnMLMeOFFKVK6Jt_0Iej21JzSAE4b0Pat9mYmpNcV7KQUvNETR-g0tNiKplUd9al-T3B-z1BYga8GeYwEpnzb1__n738uc--3WEXqSiHBYVuHFK50j6Y34JNDEQR7X2SBTebtrnLhtm0jdm2TZK92r2ge9Fdn6jfDQEWPA</recordid><startdate>20121019</startdate><enddate>20121019</enddate><creator>Alam, Md Suhail</creator><creator>Getz, Michelle</creator><creator>Safeukui, Innocent</creator><creator>Yi, Sue</creator><creator>Tamez, Pamela</creator><creator>Shin, Jenny</creator><creator>Velázquez, Peter</creator><creator>Haldar, Kasturi</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20121019</creationdate><title>Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder</title><author>Alam, Md Suhail ; Getz, Michelle ; Safeukui, Innocent ; Yi, Sue ; Tamez, Pamela ; Shin, Jenny ; Velázquez, Peter ; Haldar, Kasturi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-a53737f8adfa9b3a9f62edf4109b1b699b6e2ef295501bf9026bb7fd18c933c93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Age</topic><topic>Aging - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Alam, Md Suhail</au><au>Getz, Michelle</au><au>Safeukui, Innocent</au><au>Yi, Sue</au><au>Tamez, Pamela</au><au>Shin, Jenny</au><au>Velázquez, Peter</au><au>Haldar, Kasturi</au><au>Barsh, Gregory S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-10-19</date><risdate>2012</risdate><volume>7</volume><issue>10</issue><spage>e48273</spage><epage>e48273</epage><pages>e48273-e48273</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1(-/-) mice relative to Npc1(+/-) at an asymptomatic stage, as well as early- and late-symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher's disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1(-/-) as well as Balb/c Npc1(nmf164) mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1(-/-) mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1(-/-) spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23094108</pmid><doi>10.1371/journal.pone.0048273</doi><tpages>e48273</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2012-10, Vol.7 (10), p.e48273-e48273 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1326561449 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Age Aging - genetics Aging - immunology Aging - pathology Analysis Animal models Animals Bacteria Bacterial diseases Biology Biomarkers Biomarkers - blood Brain Brain - immunology Brain - metabolism Care and treatment Cholesterol Damage detection Diagnosis Diagnostic systems Disease Disease Progression Female Gaucher's disease Gene Expression Gene regulation Genes Genetic engineering Genomes Humans Immunity Immunity (Disease) Immunity, Innate Immunohistochemistry Infections Innate immunity Intracellular Signaling Peptides and Proteins Leukocytes (neutrophilic) Liver Liver - immunology Liver - metabolism Liver diseases Lysosomes Lysosomes - genetics Lysosomes - immunology Lysosomes - metabolism Lysozyme Male Markers Medicine Mice Mice, Knockout Muramidase - blood Muramidase - genetics Mutants Mutation Neurodegeneration Neurological diseases Neutrophil Infiltration Neutrophils Neutrophils - immunology Neutrophils - metabolism Niemann-Pick disease Niemann-Pick Disease, Type C - genetics Niemann-Pick Disease, Type C - immunology Niemann-Pick Disease, Type C - pathology Npc1 protein Organs Pathophysiology Plasma Point mutation Proteins Proteins - genetics Proteins - immunology Proteins - metabolism Salmonella Spleen Spleen - immunology Spleen - metabolism Storage Tumor necrosis factor-TNF |
| title | Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder |
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