MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias
The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2018-12, Vol.115 (52), p.E12407-E12416 |
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| creator | Brown, Alexander S. Meera, Pratap Altindag, Banu Chopra, Ravi Perkins, Emma M. Paul, Sharan Scoles, Daniel R. Tarapore, Eric Magri, Jessica Huang, Haoran Jackson, Mandy Shakkottai, Vikram G. Otis, Thomas S. Pulst, Stefan M. Atwood, Scott X. Oro, Anthony E. |
| description | The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression. |
| doi_str_mv | 10.1073/pnas.1816177115 |
| format | Article |
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The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1816177115</identifier><identifier>PMID: 30530649</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animal models ; Animals ; Apoptosis ; Ataxia ; Ataxia - pathology ; Ataxin ; Biological Sciences ; Cell culture ; Cell death ; Cytoskeleton ; Degeneration ; Disease Models, Animal ; Gene expression ; Homeostasis ; Humans ; Kinases ; Metastases ; Mice ; Mice, Inbred C57BL ; Microfilament Proteins - genetics ; Microfilament Proteins - metabolism ; Mutants ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Nervous system ; Neurodegeneration ; PNAS Plus ; Proteins ; Proteins - metabolism ; Purkinje Cells - physiology ; Spinocerebellar ataxia ; Spinocerebellar Ataxias - genetics ; Spinocerebellar Ataxias - metabolism ; Spinocerebellar Ataxias - physiopathology ; Spinocerebellar Degenerations - metabolism ; Spinocerebellar Degenerations - physiopathology ; Src protein ; src-Family Kinases - metabolism ; Therapeutic applications ; Tyrosine</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2018-12, Vol.115 (52), p.E12407-E12416</ispartof><rights>Volumes 1–89 and 106–115, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Dec 26, 2018</rights><rights>2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c443t-98aa29cd646813b28a9bde536f6499cf3599c5e273a37062116d645237bda1443</citedby><cites>FETCH-LOGICAL-c443t-98aa29cd646813b28a9bde536f6499cf3599c5e273a37062116d645237bda1443</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26573979$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26573979$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30530649$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brown, Alexander S.</creatorcontrib><creatorcontrib>Meera, Pratap</creatorcontrib><creatorcontrib>Altindag, Banu</creatorcontrib><creatorcontrib>Chopra, Ravi</creatorcontrib><creatorcontrib>Perkins, Emma M.</creatorcontrib><creatorcontrib>Paul, Sharan</creatorcontrib><creatorcontrib>Scoles, Daniel R.</creatorcontrib><creatorcontrib>Tarapore, Eric</creatorcontrib><creatorcontrib>Magri, Jessica</creatorcontrib><creatorcontrib>Huang, Haoran</creatorcontrib><creatorcontrib>Jackson, Mandy</creatorcontrib><creatorcontrib>Shakkottai, Vikram G.</creatorcontrib><creatorcontrib>Otis, Thomas S.</creatorcontrib><creatorcontrib>Pulst, Stefan M.</creatorcontrib><creatorcontrib>Atwood, Scott X.</creatorcontrib><creatorcontrib>Oro, Anthony E.</creatorcontrib><title>MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.</description><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Ataxia</subject><subject>Ataxia - pathology</subject><subject>Ataxin</subject><subject>Biological Sciences</subject><subject>Cell culture</subject><subject>Cell death</subject><subject>Cytoskeleton</subject><subject>Degeneration</subject><subject>Disease Models, Animal</subject><subject>Gene expression</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Kinases</subject><subject>Metastases</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Microfilament Proteins - genetics</subject><subject>Microfilament Proteins - metabolism</subject><subject>Mutants</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Nervous system</subject><subject>Neurodegeneration</subject><subject>PNAS Plus</subject><subject>Proteins</subject><subject>Proteins - metabolism</subject><subject>Purkinje Cells - physiology</subject><subject>Spinocerebellar ataxia</subject><subject>Spinocerebellar Ataxias - genetics</subject><subject>Spinocerebellar Ataxias - metabolism</subject><subject>Spinocerebellar Ataxias - physiopathology</subject><subject>Spinocerebellar Degenerations - metabolism</subject><subject>Spinocerebellar Degenerations - physiopathology</subject><subject>Src protein</subject><subject>src-Family Kinases - metabolism</subject><subject>Therapeutic applications</subject><subject>Tyrosine</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkbtPwzAQhy0EgvKYmUCRWFjS-uzYjhckhHgKxNAyW27igIuTFDtB9L_HVaE8lrvhPn-68w-hQ8BDwIKO5o0OQ8iBgxAAbAMNAEtIeSbxJhpgTESaZyTbQbshzDDGkuV4G-1QzCiO0ADdPUzGYxiNfZFUurZukbza6DRJuQjePPdOd7Ztkr4pjXfWhKTuXWfnziS2eTHedqZMdKc_rA77aKvSLpiDr76Hnq4uJxc36f3j9e3F-X1aZBntUplrTWRR8oznQKck13JaGkZ5FReSRUVZrMwQQTUVmBMAHllGqJiWGqJiD52tvPN-WpuyME3ntVNzb2vtF6rVVv2dNPZFPbfvilPAOVsKTr8Evn3rTehUbUNhnNONafugCDAGDDijET35h87a3jfxvEhxkjEuWB6p0YoqfBvit1XrZQCrZU5qmZP6ySm-OP59w5r_DiYCRytgFrrWr-eEM0GlkPQTU8eYKQ</recordid><startdate>20181226</startdate><enddate>20181226</enddate><creator>Brown, Alexander S.</creator><creator>Meera, Pratap</creator><creator>Altindag, Banu</creator><creator>Chopra, Ravi</creator><creator>Perkins, Emma M.</creator><creator>Paul, Sharan</creator><creator>Scoles, Daniel R.</creator><creator>Tarapore, Eric</creator><creator>Magri, Jessica</creator><creator>Huang, Haoran</creator><creator>Jackson, Mandy</creator><creator>Shakkottai, Vikram G.</creator><creator>Otis, Thomas S.</creator><creator>Pulst, Stefan M.</creator><creator>Atwood, Scott X.</creator><creator>Oro, Anthony E.</creator><general>National Academy of Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</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>20181226</creationdate><title>MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias</title><author>Brown, Alexander S. ; Meera, Pratap ; Altindag, Banu ; Chopra, Ravi ; Perkins, Emma M. ; Paul, Sharan ; Scoles, Daniel R. ; Tarapore, Eric ; Magri, Jessica ; Huang, Haoran ; Jackson, Mandy ; Shakkottai, Vikram G. ; Otis, Thomas S. ; Pulst, Stefan M. ; Atwood, Scott X. ; Oro, Anthony E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c443t-98aa29cd646813b28a9bde536f6499cf3599c5e273a37062116d645237bda1443</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Ataxia</topic><topic>Ataxia - pathology</topic><topic>Ataxin</topic><topic>Biological Sciences</topic><topic>Cell culture</topic><topic>Cell death</topic><topic>Cytoskeleton</topic><topic>Degeneration</topic><topic>Disease Models, Animal</topic><topic>Gene expression</topic><topic>Homeostasis</topic><topic>Humans</topic><topic>Kinases</topic><topic>Metastases</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Microfilament Proteins - genetics</topic><topic>Microfilament Proteins - metabolism</topic><topic>Mutants</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Nervous system</topic><topic>Neurodegeneration</topic><topic>PNAS Plus</topic><topic>Proteins</topic><topic>Proteins - metabolism</topic><topic>Purkinje Cells - physiology</topic><topic>Spinocerebellar ataxia</topic><topic>Spinocerebellar Ataxias - genetics</topic><topic>Spinocerebellar Ataxias - metabolism</topic><topic>Spinocerebellar Ataxias - physiopathology</topic><topic>Spinocerebellar Degenerations - metabolism</topic><topic>Spinocerebellar Degenerations - physiopathology</topic><topic>Src protein</topic><topic>src-Family Kinases - metabolism</topic><topic>Therapeutic applications</topic><topic>Tyrosine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brown, Alexander S.</creatorcontrib><creatorcontrib>Meera, Pratap</creatorcontrib><creatorcontrib>Altindag, Banu</creatorcontrib><creatorcontrib>Chopra, Ravi</creatorcontrib><creatorcontrib>Perkins, Emma M.</creatorcontrib><creatorcontrib>Paul, Sharan</creatorcontrib><creatorcontrib>Scoles, Daniel R.</creatorcontrib><creatorcontrib>Tarapore, Eric</creatorcontrib><creatorcontrib>Magri, Jessica</creatorcontrib><creatorcontrib>Huang, Haoran</creatorcontrib><creatorcontrib>Jackson, Mandy</creatorcontrib><creatorcontrib>Shakkottai, Vikram G.</creatorcontrib><creatorcontrib>Otis, Thomas S.</creatorcontrib><creatorcontrib>Pulst, Stefan M.</creatorcontrib><creatorcontrib>Atwood, Scott X.</creatorcontrib><creatorcontrib>Oro, Anthony E.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brown, Alexander S.</au><au>Meera, Pratap</au><au>Altindag, Banu</au><au>Chopra, Ravi</au><au>Perkins, Emma M.</au><au>Paul, Sharan</au><au>Scoles, Daniel R.</au><au>Tarapore, Eric</au><au>Magri, Jessica</au><au>Huang, Haoran</au><au>Jackson, Mandy</au><au>Shakkottai, Vikram G.</au><au>Otis, Thomas S.</au><au>Pulst, Stefan M.</au><au>Atwood, Scott X.</au><au>Oro, Anthony E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2018-12-26</date><risdate>2018</risdate><volume>115</volume><issue>52</issue><spage>E12407</spage><epage>E12416</epage><pages>E12407-E12416</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>30530649</pmid><doi>10.1073/pnas.1816177115</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animal models Animals Apoptosis Ataxia Ataxia - pathology Ataxin Biological Sciences Cell culture Cell death Cytoskeleton Degeneration Disease Models, Animal Gene expression Homeostasis Humans Kinases Metastases Mice Mice, Inbred C57BL Microfilament Proteins - genetics Microfilament Proteins - metabolism Mutants Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Nervous system Neurodegeneration PNAS Plus Proteins Proteins - metabolism Purkinje Cells - physiology Spinocerebellar ataxia Spinocerebellar Ataxias - genetics Spinocerebellar Ataxias - metabolism Spinocerebellar Ataxias - physiopathology Spinocerebellar Degenerations - metabolism Spinocerebellar Degenerations - physiopathology Src protein src-Family Kinases - metabolism Therapeutic applications Tyrosine |
| title | MTSS1/Src family kinase dysregulation underlies multiple inherited ataxias |
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