Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease.
Identifieur interne : 000290 ( PubMed/Corpus ); précédent : 000289; suivant : 000291Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease.
Auteurs : Karen E. Murphy ; Amanda M. Gysbers ; Sarah K. Abbott ; Adena S. Spiro ; Akiko Furuta ; Antony Cooper ; Brett Garner ; Tomohiro Kabuta ; Glenda M. HallidaySource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2015.
Abstract
Lysosomes are the primary catabolic compartment for the degradation of intracellular proteins through autophagy. The presence of abnormal intracellular α-synuclein-positive aggregates in Parkinson's disease (PD) indicates that the degradative capacity of lysosomes is impaired in PD. Specific dysfunction of chaperone-mediated autophagy (CMA) in PD is suggested by reductions in the CMA membrane receptor, lysosomal-associated membrane protein (LAMP) 2A, although whether LAMP2A is the only LAMP2 isoform affected by PD is unknown. Messenger RNA (mRNA) and protein expression of all three LAMP2 isoforms was assessed in brain extracts from regions with and without PD-related increases in α-synuclein in autopsy samples from subjects in the early pathological stage of PD (n = 9), compared to age- and postmortem delay-matched controls (n = 10). In the early stages of PD, mRNA expression of all LAMP2 isoforms was not different from controls, with LAMP2B and LAMP2C protein levels also unchanged in PD. The selective loss of LAMP2A protein directly correlated with the increased levels of α-synuclein and decreased levels of the CMA chaperone heat shock cognate protein 70 in the same PD samples, as well as with the accumulation of cytosolic CMA substrate proteins. Our data show that LAMP2 protein isoforms are differentially affected in the early stages of PD, with LAMP2A selectively reduced in association with increased α-synuclein, and suggests that dysregulation of CMA-mediated protein degradation occurs before substantial α-synuclein aggregation in PD. © 2015 International Parkinson and Movement Disorder Society.
DOI: 10.1002/mds.26141
PubMed: 25594542
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Abbott</name><affiliation><nlm:affiliation>Illawarra Health and Medical Research Institute, Wollongong, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Spiro, Adena S" sort="Spiro, Adena S" uniqKey="Spiro A" first="Adena S" last="Spiro">Adena S. Spiro</name><affiliation><nlm:affiliation>Illawarra Health and Medical Research Institute, Wollongong, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Furuta, Akiko" sort="Furuta, Akiko" uniqKey="Furuta A" first="Akiko" last="Furuta">Akiko Furuta</name><affiliation><nlm:affiliation>Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Cooper, Antony" sort="Cooper, Antony" uniqKey="Cooper A" first="Antony" last="Cooper">Antony Cooper</name><affiliation><nlm:affiliation>The Garvan Institute of Medical Research, Sydney, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Garner, Brett" sort="Garner, Brett" uniqKey="Garner B" first="Brett" last="Garner">Brett Garner</name><affiliation><nlm:affiliation>Illawarra Health and Medical Research Institute, Wollongong, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Kabuta, Tomohiro" sort="Kabuta, Tomohiro" uniqKey="Kabuta T" first="Tomohiro" last="Kabuta">Tomohiro Kabuta</name><affiliation><nlm:affiliation>Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Halliday, Glenda M" sort="Halliday, Glenda M" uniqKey="Halliday G" first="Glenda M" last="Halliday">Glenda M. 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Gysbers</name><affiliation><nlm:affiliation>Neuroscience Research Australia, Sydney, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Abbott, Sarah K" sort="Abbott, Sarah K" uniqKey="Abbott S" first="Sarah K" last="Abbott">Sarah K. Abbott</name><affiliation><nlm:affiliation>Illawarra Health and Medical Research Institute, Wollongong, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Spiro, Adena S" sort="Spiro, Adena S" uniqKey="Spiro A" first="Adena S" last="Spiro">Adena S. Spiro</name><affiliation><nlm:affiliation>Illawarra Health and Medical Research Institute, Wollongong, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Furuta, Akiko" sort="Furuta, Akiko" uniqKey="Furuta A" first="Akiko" last="Furuta">Akiko Furuta</name><affiliation><nlm:affiliation>Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Cooper, Antony" sort="Cooper, Antony" uniqKey="Cooper A" first="Antony" last="Cooper">Antony Cooper</name><affiliation><nlm:affiliation>The Garvan Institute of Medical Research, Sydney, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Garner, Brett" sort="Garner, Brett" uniqKey="Garner B" first="Brett" last="Garner">Brett Garner</name><affiliation><nlm:affiliation>Illawarra Health and Medical Research Institute, Wollongong, Australia.</nlm:affiliation></affiliation></author><author><name sortKey="Kabuta, Tomohiro" sort="Kabuta, Tomohiro" uniqKey="Kabuta T" first="Tomohiro" last="Kabuta">Tomohiro Kabuta</name><affiliation><nlm:affiliation>Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.</nlm:affiliation></affiliation></author><author><name sortKey="Halliday, Glenda M" sort="Halliday, Glenda M" uniqKey="Halliday G" first="Glenda M" last="Halliday">Glenda M. Halliday</name><affiliation><nlm:affiliation>Neuroscience Research Australia, Sydney, Australia.</nlm:affiliation></affiliation></author></analytic><series><title level="j">Movement disorders : official journal of the Movement Disorder Society</title><idno type="eISSN">1531-8257</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Lysosomes are the primary catabolic compartment for the degradation of intracellular proteins through autophagy. The presence of abnormal intracellular α-synuclein-positive aggregates in Parkinson's disease (PD) indicates that the degradative capacity of lysosomes is impaired in PD. Specific dysfunction of chaperone-mediated autophagy (CMA) in PD is suggested by reductions in the CMA membrane receptor, lysosomal-associated membrane protein (LAMP) 2A, although whether LAMP2A is the only LAMP2 isoform affected by PD is unknown. Messenger RNA (mRNA) and protein expression of all three LAMP2 isoforms was assessed in brain extracts from regions with and without PD-related increases in α-synuclein in autopsy samples from subjects in the early pathological stage of PD (n = 9), compared to age- and postmortem delay-matched controls (n = 10). In the early stages of PD, mRNA expression of all LAMP2 isoforms was not different from controls, with LAMP2B and LAMP2C protein levels also unchanged in PD. The selective loss of LAMP2A protein directly correlated with the increased levels of α-synuclein and decreased levels of the CMA chaperone heat shock cognate protein 70 in the same PD samples, as well as with the accumulation of cytosolic CMA substrate proteins. Our data show that LAMP2 protein isoforms are differentially affected in the early stages of PD, with LAMP2A selectively reduced in association with increased α-synuclein, and suggests that dysregulation of CMA-mediated protein degradation occurs before substantial α-synuclein aggregation in PD. © 2015 International Parkinson and Movement Disorder Society.</div></front></TEI><pubmed><MedlineCitation Owner="NLM" Status="In-Data-Review"><PMID Version="1">25594542</PMID><DateCreated><Year>2015</Year><Month>10</Month><Day>17</Day></DateCreated><Article PubModel="Print-Electronic"><Journal><ISSN IssnType="Electronic">1531-8257</ISSN><JournalIssue CitedMedium="Internet"><Volume>30</Volume><Issue>12</Issue><PubDate><Year>2015</Year><Month>Oct</Month></PubDate></JournalIssue><Title>Movement disorders : official journal of the Movement Disorder Society</Title><ISOAbbreviation>Mov. Disord.</ISOAbbreviation></Journal><ArticleTitle>Lysosomal-associated membrane protein 2 isoforms are differentially affected in early Parkinson's disease.</ArticleTitle><Pagination><MedlinePgn>1639-47</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1002/mds.26141</ELocationID><Abstract><AbstractText>Lysosomes are the primary catabolic compartment for the degradation of intracellular proteins through autophagy. The presence of abnormal intracellular α-synuclein-positive aggregates in Parkinson's disease (PD) indicates that the degradative capacity of lysosomes is impaired in PD. Specific dysfunction of chaperone-mediated autophagy (CMA) in PD is suggested by reductions in the CMA membrane receptor, lysosomal-associated membrane protein (LAMP) 2A, although whether LAMP2A is the only LAMP2 isoform affected by PD is unknown. Messenger RNA (mRNA) and protein expression of all three LAMP2 isoforms was assessed in brain extracts from regions with and without PD-related increases in α-synuclein in autopsy samples from subjects in the early pathological stage of PD (n = 9), compared to age- and postmortem delay-matched controls (n = 10). In the early stages of PD, mRNA expression of all LAMP2 isoforms was not different from controls, with LAMP2B and LAMP2C protein levels also unchanged in PD. The selective loss of LAMP2A protein directly correlated with the increased levels of α-synuclein and decreased levels of the CMA chaperone heat shock cognate protein 70 in the same PD samples, as well as with the accumulation of cytosolic CMA substrate proteins. Our data show that LAMP2 protein isoforms are differentially affected in the early stages of PD, with LAMP2A selectively reduced in association with increased α-synuclein, and suggests that dysregulation of CMA-mediated protein degradation occurs before substantial α-synuclein aggregation in PD. © 2015 International Parkinson and Movement Disorder Society.</AbstractText><CopyrightInformation>© 2015 International Parkinson and Movement Disorder Society.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Murphy</LastName><ForeName>Karen E</ForeName><Initials>KE</Initials><AffiliationInfo><Affiliation>Neuroscience Research Australia, Sydney, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gysbers</LastName><ForeName>Amanda M</ForeName><Initials>AM</Initials><AffiliationInfo><Affiliation>Neuroscience Research Australia, Sydney, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Abbott</LastName><ForeName>Sarah K</ForeName><Initials>SK</Initials><AffiliationInfo><Affiliation>Illawarra Health and Medical Research Institute, Wollongong, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Spiro</LastName><ForeName>Adena S</ForeName><Initials>AS</Initials><AffiliationInfo><Affiliation>Illawarra Health and Medical Research Institute, Wollongong, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Furuta</LastName><ForeName>Akiko</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Cooper</LastName><ForeName>Antony</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>The Garvan Institute of Medical Research, Sydney, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>St Vincent's Clinical School, Faculty of Medicine, and School of Biotechnology and Biomolecular Sciences, Faculty of Science, The University of New South Wales, Sydney, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Garner</LastName><ForeName>Brett</ForeName><Initials>B</Initials><AffiliationInfo><Affiliation>Illawarra Health and Medical Research Institute, Wollongong, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kabuta</LastName><ForeName>Tomohiro</ForeName><Initials>T</Initials><AffiliationInfo><Affiliation>Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Halliday</LastName><ForeName>Glenda M</ForeName><Initials>GM</Initials><AffiliationInfo><Affiliation>Neuroscience Research Australia, Sydney, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, Australia.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2015</Year><Month>01</Month><Day>16</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>Mov Disord</MedlineTA><NlmUniqueID>8610688</NlmUniqueID><ISSNLinking>0885-3185</ISSNLinking></MedlineJournalInfo><CitationSubset>IM</CitationSubset><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">LAMP2</Keyword><Keyword MajorTopicYN="N">Parkinson's disease</Keyword><Keyword MajorTopicYN="N">chaperone-mediated autophagy (CMA)</Keyword><Keyword MajorTopicYN="N">nucleic acid autophagy</Keyword><Keyword MajorTopicYN="N">α-synuclein</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2014</Year><Month>8</Month><Day>22</Day></PubMedPubDate><PubMedPubDate 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