Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy
Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocy...
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| Veröffentlicht in: | Acta neuropathologica 2020-04, Vol.139 (4), p.735-771 |
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| creator | Ferrer, Isidro Andrés-Benito, Pol Zelaya, Maria Victoria Aguirre, Maria Elena Erro Carmona, Margarita Ausín, Karina Lachén-Montes, Mercedes Fernández-Irigoyen, Joaquín Santamaría, Enrique del Rio, José Antonio |
| description | Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in
MAPT
and one case of sporadic GGT (sGGT) and one case of GGT linked to
MAPT
K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to
MAPT
P301T mutation, astrocyte markers
GFAP
,
ALDH1L1
,
YKL40
mRNA and protein,
GJA1
mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers
OLIG1
and
OLIG2
mRNA,
and myelin-related genes
MBP
,
PLP1
,
CNP
,
MAG
,
MAL
,
MOG,
and
MOBP
are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to
MAPT
K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to
MAPT
P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to
MAPT
P301T, sGGT, and GGT linked to
MAPT
K317 |
| doi_str_mv | 10.1007/s00401-019-02122-9 |
| format | Article |
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MAPT
and one case of sporadic GGT (sGGT) and one case of GGT linked to
MAPT
K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to
MAPT
P301T mutation, astrocyte markers
GFAP
,
ALDH1L1
,
YKL40
mRNA and protein,
GJA1
mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers
OLIG1
and
OLIG2
mRNA,
and myelin-related genes
MBP
,
PLP1
,
CNP
,
MAG
,
MAL
,
MOG,
and
MOBP
are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to
MAPT
K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to
MAPT
P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to
MAPT
P301T, sGGT, and GGT linked to
MAPT
K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.</description><identifier>ISSN: 0001-6322</identifier><identifier>EISSN: 1432-0533</identifier><identifier>DOI: 10.1007/s00401-019-02122-9</identifier><identifier>PMID: 31907603</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Adult ; Animals ; Antibodies ; Brain ; Brain - metabolism ; Brain - pathology ; Comparative analysis ; Connexin 43 ; Corpus callosum ; Cortex (frontal) ; Female ; Gap junctions ; Genetic aspects ; Genetic research ; Glial cells ; Glial fibrillary acidic protein ; Glucose transporter ; Glutamate ; Glutamic acid transporter ; Humans ; Immunohistochemistry ; Inoculation ; Male ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Mitochondria ; Morphogenesis ; Mutation ; Myelin ; Myelin proteolipid protein ; Myelin-associated glycoprotein ; Nervous system diseases ; Neurodegenerative diseases ; Neuroglia - metabolism ; Neuroglia - pathology ; Neuronal-glial interactions ; Neurons ; Neurons - metabolism ; Neurons - pathology ; Neurosciences ; Oligodendrocyte-myelin glycoprotein ; Original Paper ; Pathology ; Phenotypes ; Phosphorylation ; Proteins ; Proteomics ; Substantia alba ; Substantia grisea ; Synaptic transmission ; tau Proteins - genetics ; tau Proteins - metabolism ; Tauopathies - genetics ; Tauopathies - metabolism ; Tauopathies - pathology ; Western blotting</subject><ispartof>Acta neuropathologica, 2020-04, Vol.139 (4), p.735-771</ispartof><rights>The Author(s) 2020</rights><rights>COPYRIGHT 2020 Springer</rights><rights>Acta Neuropathologica is a copyright of Springer, (2020). All Rights Reserved. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c541t-5e3d10bbee80b8dcf54072f30ecbc1379b633aabf292fc4c7fc722db192d561e3</citedby><cites>FETCH-LOGICAL-c541t-5e3d10bbee80b8dcf54072f30ecbc1379b633aabf292fc4c7fc722db192d561e3</cites><orcidid>0000-0001-9888-8754</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00401-019-02122-9$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00401-019-02122-9$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31907603$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ferrer, Isidro</creatorcontrib><creatorcontrib>Andrés-Benito, Pol</creatorcontrib><creatorcontrib>Zelaya, Maria Victoria</creatorcontrib><creatorcontrib>Aguirre, Maria Elena Erro</creatorcontrib><creatorcontrib>Carmona, Margarita</creatorcontrib><creatorcontrib>Ausín, Karina</creatorcontrib><creatorcontrib>Lachén-Montes, Mercedes</creatorcontrib><creatorcontrib>Fernández-Irigoyen, Joaquín</creatorcontrib><creatorcontrib>Santamaría, Enrique</creatorcontrib><creatorcontrib>del Rio, José Antonio</creatorcontrib><title>Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy</title><title>Acta neuropathologica</title><addtitle>Acta Neuropathol</addtitle><addtitle>Acta Neuropathol</addtitle><description>Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in
MAPT
and one case of sporadic GGT (sGGT) and one case of GGT linked to
MAPT
K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to
MAPT
P301T mutation, astrocyte markers
GFAP
,
ALDH1L1
,
YKL40
mRNA and protein,
GJA1
mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers
OLIG1
and
OLIG2
mRNA,
and myelin-related genes
MBP
,
PLP1
,
CNP
,
MAG
,
MAL
,
MOG,
and
MOBP
are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to
MAPT
K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to
MAPT
P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to
MAPT
P301T, sGGT, and GGT linked to
MAPT
K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.</description><subject>Adult</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Brain</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Comparative analysis</subject><subject>Connexin 43</subject><subject>Corpus callosum</subject><subject>Cortex (frontal)</subject><subject>Female</subject><subject>Gap junctions</subject><subject>Genetic aspects</subject><subject>Genetic research</subject><subject>Glial cells</subject><subject>Glial fibrillary acidic protein</subject><subject>Glucose transporter</subject><subject>Glutamate</subject><subject>Glutamic acid transporter</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Inoculation</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Middle Aged</subject><subject>Mitochondria</subject><subject>Morphogenesis</subject><subject>Mutation</subject><subject>Myelin</subject><subject>Myelin proteolipid protein</subject><subject>Myelin-associated glycoprotein</subject><subject>Nervous system diseases</subject><subject>Neurodegenerative diseases</subject><subject>Neuroglia - metabolism</subject><subject>Neuroglia - pathology</subject><subject>Neuronal-glial interactions</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Neurosciences</subject><subject>Oligodendrocyte-myelin glycoprotein</subject><subject>Original Paper</subject><subject>Pathology</subject><subject>Phenotypes</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Proteomics</subject><subject>Substantia alba</subject><subject>Substantia grisea</subject><subject>Synaptic transmission</subject><subject>tau Proteins - genetics</subject><subject>tau Proteins - metabolism</subject><subject>Tauopathies - genetics</subject><subject>Tauopathies - metabolism</subject><subject>Tauopathies - pathology</subject><subject>Western blotting</subject><issn>0001-6322</issn><issn>1432-0533</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9ks1u1TAQhS0EopfCC7BAltiwSfFP_swC6aqigFQEi7K2HGeSujh2sB3EfRmeFefe0tIKIS_iyXznjMY6CD2n5IQS0ryOhJSEFoSKgjDKWCEeoA0tOStIxflDtCEkt2vO2BF6EuNVrlhTVo_REaeCNDXhG_TrTE3GGmXxaH23WBXyZS2TWvys0uUOW-O-QY-Tx5-2Xy7wtCSVjHfxDZ68Bb3XOFjCHvfWjzusXI8jQG_ciLWalTZph_2AFZ6DTz7tZqPzjMn8zMZ7rcvlqro3_Cl6NCgb4dn19xh9PXt3cfqhOP_8_uPp9rzQVUlTUQHvKek6gJZ0ba-HqiQNGzgB3WnKG9HVnCvVDUywQZe6GXTDWN9RwfqqpsCP0duD77x0E_QaXArKyjmYSYWd9MrIux1nLuXof8iGiJrXIhu8ujYI_vsCMcnJRA3WKgd-iZJxXjJWcUIz-vIeeuWXkB9gpVomeMVafkuNyoI0bvB5rl5N5bambSXKtmwzdfIPKp8eJqO9g8Hk_3cE7CDQwccYYLjZkRK5pkoeUiVzquQ-VXJd7sXfr3Mj-ROjDPADEHPLjRBuV_qP7W-WTdtM</recordid><startdate>20200401</startdate><enddate>20200401</enddate><creator>Ferrer, Isidro</creator><creator>Andrés-Benito, Pol</creator><creator>Zelaya, Maria Victoria</creator><creator>Aguirre, Maria Elena Erro</creator><creator>Carmona, Margarita</creator><creator>Ausín, Karina</creator><creator>Lachén-Montes, Mercedes</creator><creator>Fernández-Irigoyen, Joaquín</creator><creator>Santamaría, Enrique</creator><creator>del Rio, José Antonio</creator><general>Springer Berlin Heidelberg</general><general>Springer</general><general>Springer Nature B.V</general><scope>C6C</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>3V.</scope><scope>7TK</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9888-8754</orcidid></search><sort><creationdate>20200401</creationdate><title>Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy</title><author>Ferrer, Isidro ; Andrés-Benito, Pol ; Zelaya, Maria Victoria ; Aguirre, Maria Elena Erro ; Carmona, Margarita ; Ausín, Karina ; Lachén-Montes, Mercedes ; Fernández-Irigoyen, Joaquín ; Santamaría, Enrique ; del Rio, José Antonio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c541t-5e3d10bbee80b8dcf54072f30ecbc1379b633aabf292fc4c7fc722db192d561e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Adult</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Brain</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Comparative analysis</topic><topic>Connexin 43</topic><topic>Corpus callosum</topic><topic>Cortex (frontal)</topic><topic>Female</topic><topic>Gap junctions</topic><topic>Genetic aspects</topic><topic>Genetic research</topic><topic>Glial cells</topic><topic>Glial fibrillary acidic protein</topic><topic>Glucose transporter</topic><topic>Glutamate</topic><topic>Glutamic acid transporter</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Inoculation</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Middle Aged</topic><topic>Mitochondria</topic><topic>Morphogenesis</topic><topic>Mutation</topic><topic>Myelin</topic><topic>Myelin proteolipid protein</topic><topic>Myelin-associated glycoprotein</topic><topic>Nervous system diseases</topic><topic>Neurodegenerative diseases</topic><topic>Neuroglia - metabolism</topic><topic>Neuroglia - pathology</topic><topic>Neuronal-glial interactions</topic><topic>Neurons</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Neurosciences</topic><topic>Oligodendrocyte-myelin glycoprotein</topic><topic>Original Paper</topic><topic>Pathology</topic><topic>Phenotypes</topic><topic>Phosphorylation</topic><topic>Proteins</topic><topic>Proteomics</topic><topic>Substantia alba</topic><topic>Substantia grisea</topic><topic>Synaptic transmission</topic><topic>tau Proteins - genetics</topic><topic>tau Proteins - metabolism</topic><topic>Tauopathies - genetics</topic><topic>Tauopathies - metabolism</topic><topic>Tauopathies - pathology</topic><topic>Western blotting</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ferrer, Isidro</creatorcontrib><creatorcontrib>Andrés-Benito, Pol</creatorcontrib><creatorcontrib>Zelaya, Maria Victoria</creatorcontrib><creatorcontrib>Aguirre, Maria Elena Erro</creatorcontrib><creatorcontrib>Carmona, Margarita</creatorcontrib><creatorcontrib>Ausín, Karina</creatorcontrib><creatorcontrib>Lachén-Montes, Mercedes</creatorcontrib><creatorcontrib>Fernández-Irigoyen, Joaquín</creatorcontrib><creatorcontrib>Santamaría, Enrique</creatorcontrib><creatorcontrib>del Rio, José Antonio</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Psychology 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>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Acta neuropathologica</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ferrer, Isidro</au><au>Andrés-Benito, Pol</au><au>Zelaya, Maria Victoria</au><au>Aguirre, Maria Elena Erro</au><au>Carmona, Margarita</au><au>Ausín, Karina</au><au>Lachén-Montes, Mercedes</au><au>Fernández-Irigoyen, Joaquín</au><au>Santamaría, Enrique</au><au>del Rio, José Antonio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy</atitle><jtitle>Acta neuropathologica</jtitle><stitle>Acta Neuropathol</stitle><addtitle>Acta Neuropathol</addtitle><date>2020-04-01</date><risdate>2020</risdate><volume>139</volume><issue>4</issue><spage>735</spage><epage>771</epage><pages>735-771</pages><issn>0001-6322</issn><eissn>1432-0533</eissn><abstract>Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in
MAPT
and one case of sporadic GGT (sGGT) and one case of GGT linked to
MAPT
K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to
MAPT
P301T mutation, astrocyte markers
GFAP
,
ALDH1L1
,
YKL40
mRNA and protein,
GJA1
mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers
OLIG1
and
OLIG2
mRNA,
and myelin-related genes
MBP
,
PLP1
,
CNP
,
MAG
,
MAL
,
MOG,
and
MOBP
are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to
MAPT
K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to
MAPT
P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to
MAPT
P301T, sGGT, and GGT linked to
MAPT
K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>31907603</pmid><doi>10.1007/s00401-019-02122-9</doi><tpages>37</tpages><orcidid>https://orcid.org/0000-0001-9888-8754</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0001-6322 |
| ispartof | Acta neuropathologica, 2020-04, Vol.139 (4), p.735-771 |
| issn | 0001-6322 1432-0533 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7096369 |
| source | MEDLINE; SpringerNature Complete Journals |
| subjects | Adult Animals Antibodies Brain Brain - metabolism Brain - pathology Comparative analysis Connexin 43 Corpus callosum Cortex (frontal) Female Gap junctions Genetic aspects Genetic research Glial cells Glial fibrillary acidic protein Glucose transporter Glutamate Glutamic acid transporter Humans Immunohistochemistry Inoculation Male Medicine Medicine & Public Health Mice Mice, Inbred C57BL Middle Aged Mitochondria Morphogenesis Mutation Myelin Myelin proteolipid protein Myelin-associated glycoprotein Nervous system diseases Neurodegenerative diseases Neuroglia - metabolism Neuroglia - pathology Neuronal-glial interactions Neurons Neurons - metabolism Neurons - pathology Neurosciences Oligodendrocyte-myelin glycoprotein Original Paper Pathology Phenotypes Phosphorylation Proteins Proteomics Substantia alba Substantia grisea Synaptic transmission tau Proteins - genetics tau Proteins - metabolism Tauopathies - genetics Tauopathies - metabolism Tauopathies - pathology Western blotting |
| title | Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T02%3A27%3A05IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Familial%20globular%20glial%20tauopathy%20linked%20to%20MAPT%20mutations:%20molecular%20neuropathology%20and%20seeding%20capacity%20of%20a%20prototypical%20mixed%20neuronal%20and%20glial%20tauopathy&rft.jtitle=Acta%20neuropathologica&rft.au=Ferrer,%20Isidro&rft.date=2020-04-01&rft.volume=139&rft.issue=4&rft.spage=735&rft.epage=771&rft.pages=735-771&rft.issn=0001-6322&rft.eissn=1432-0533&rft_id=info:doi/10.1007/s00401-019-02122-9&rft_dat=%3Cgale_pubme%3EA618594848%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2382935283&rft_id=info:pmid/31907603&rft_galeid=A618594848&rfr_iscdi=true |