TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau
Identifieur interne : 005596 ( Main/Exploration ); précédent : 005595; suivant : 005597TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau
Auteurs : Maxime Wc Rousseaux [États-Unis] ; Maria De Haro [États-Unis] ; Cristian A. Lasagna-Reeves [États-Unis] ; Antonia De Maio [États-Unis, Canada] ; Jeehye Park [États-Unis] ; Paymaan Jafar-Nejad [États-Unis] ; Ismael Al-Ramahi [États-Unis] ; Ajay Sharma [États-Unis] ; Lauren See [États-Unis] ; Nan Lu [États-Unis] ; Luis Vilanova-Velez [États-Unis] ; Tiemo J. Klisch [États-Unis] ; Thomas F. Westbrook [États-Unis] ; Juan C. Troncoso [États-Unis] ; Juan Botas [États-Unis] ; Huda Y. Zoghbi [États-Unis, Canada]Source :
- eLife [ 2050-084X ] ; ????.
Abstract
Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that α-Syn and tau overlap pathologically. The connections between α-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of α-Syn and tau. We found that TRIM28 regulates α-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and α-Syn-mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points.
Url:
DOI: 10.7554/eLife.19809
PubMed: 27779468
PubMed Central: 5104516
Affiliations:
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Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Jafar Nejad, Paymaan" sort="Jafar Nejad, Paymaan" uniqKey="Jafar Nejad P" first="Paymaan" last="Jafar-Nejad">Paymaan Jafar-Nejad</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Al Ramahi, Ismael" sort="Al Ramahi, Ismael" uniqKey="Al Ramahi I" first="Ismael" last="Al-Ramahi">Ismael Al-Ramahi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sharma, Ajay" sort="Sharma, Ajay" uniqKey="Sharma A" first="Ajay" last="Sharma">Ajay Sharma</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United 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and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Klisch, Tiemo J" sort="Klisch, Tiemo J" uniqKey="Klisch T" first="Tiemo J" last="Klisch">Tiemo J. Klisch</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Westbrook, Thomas F" sort="Westbrook, Thomas F" uniqKey="Westbrook T" first="Thomas F" last="Westbrook">Thomas F. Westbrook</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><institution content-type="dept">The Verna and Marrs McLean Department of Biochemistry and Molecular Biology</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Troncoso, Juan C" sort="Troncoso, Juan C" uniqKey="Troncoso J" first="Juan C" last="Troncoso">Juan C. Troncoso</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution content-type="dept">Division of Neuropathology, Department of Pathology</institution>,<institution>Johns Hopkins University School of Medicine</institution>,<addr-line>Baltimore</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Botas, Juan" sort="Botas, Juan" uniqKey="Botas J" first="Juan" last="Botas">Juan Botas</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zoghbi, Huda Y" sort="Zoghbi, Huda Y" uniqKey="Zoghbi H" first="Huda Y" last="Zoghbi">Huda Y. 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Medicine</institution>,<addr-line>Houston</addr-line>,<country>Canada</country></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><institution content-type="dept">Howard Hughes Medical Institute</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">27779468</idno><idno type="pmc">5104516</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104516</idno><idno type="RBID">PMC:5104516</idno><idno type="doi">10.7554/eLife.19809</idno><date when="????">????</date><idno type="wicri:Area/Pmc/Corpus">000B49</idno><idno type="wicri:explorRef" wicri:stream="Pmc" 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Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="De Haro, Maria" sort="De Haro, Maria" uniqKey="De Haro M" first="Maria" last="De Haro">Maria De Haro</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lasagna Reeves, Cristian A" sort="Lasagna Reeves, Cristian A" uniqKey="Lasagna Reeves C" first="Cristian A" last="Lasagna-Reeves">Cristian A. Lasagna-Reeves</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="De Maio, Antonia" sort="De Maio, Antonia" uniqKey="De Maio A" first="Antonia" last="De Maio">Antonia De Maio</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution content-type="dept">Program in Developmental Biology</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>Canada</country></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Park, Jeehye" sort="Park, Jeehye" uniqKey="Park J" first="Jeehye" last="Park">Jeehye Park</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Jafar Nejad, Paymaan" sort="Jafar Nejad, Paymaan" uniqKey="Jafar Nejad P" first="Paymaan" last="Jafar-Nejad">Paymaan Jafar-Nejad</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Al Ramahi, Ismael" sort="Al Ramahi, Ismael" uniqKey="Al Ramahi I" first="Ismael" last="Al-Ramahi">Ismael Al-Ramahi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Sharma, Ajay" sort="Sharma, Ajay" uniqKey="Sharma A" first="Ajay" last="Sharma">Ajay Sharma</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="See, Lauren" sort="See, Lauren" uniqKey="See L" first="Lauren" last="See">Lauren See</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lu, Nan" sort="Lu, Nan" uniqKey="Lu N" first="Nan" last="Lu">Nan Lu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Vilanova Velez, Luis" sort="Vilanova Velez, Luis" uniqKey="Vilanova Velez L" first="Luis" last="Vilanova-Velez">Luis Vilanova-Velez</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Klisch, Tiemo J" sort="Klisch, Tiemo J" uniqKey="Klisch T" first="Tiemo J" last="Klisch">Tiemo J. Klisch</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Westbrook, Thomas F" sort="Westbrook, Thomas F" uniqKey="Westbrook T" first="Thomas F" last="Westbrook">Thomas F. Westbrook</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><institution content-type="dept">The Verna and Marrs McLean Department of Biochemistry and Molecular Biology</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Troncoso, Juan C" sort="Troncoso, Juan C" uniqKey="Troncoso J" first="Juan C" last="Troncoso">Juan C. Troncoso</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution content-type="dept">Division of Neuropathology, Department of Pathology</institution>,<institution>Johns Hopkins University School of Medicine</institution>,<addr-line>Baltimore</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Botas, Juan" sort="Botas, Juan" uniqKey="Botas J" first="Juan" last="Botas">Juan Botas</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Zoghbi, Huda Y" sort="Zoghbi, Huda Y" uniqKey="Zoghbi H" first="Huda Y" last="Zoghbi">Huda Y. Zoghbi</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution content-type="dept">Department of Molecular and Human Genetics</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution content-type="dept">Jan and Dan Duncan Neurological Research Institute</institution>,<institution>Texas Children’s Hospital</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution content-type="dept">Program in Developmental Biology</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>Canada</country></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff6"><institution content-type="dept">Howard Hughes Medical Institute</institution>,<institution>Baylor College of Medicine</institution>,<addr-line>Houston</addr-line>,<country>United States</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">eLife</title><idno type="eISSN">2050-084X</idno><imprint><date when="????">????</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Several neurodegenerative diseases are driven by the toxic gain-of-function of specific proteins within the brain. Elevated levels of alpha-synuclein (α-Syn) appear to drive neurotoxicity in Parkinson's disease (PD); neuronal accumulation of tau is a hallmark of Alzheimer's disease (AD); and their increased levels cause neurodegeneration in humans and model organisms. Despite the clinical differences between AD and PD, several lines of evidence suggest that α-Syn and tau overlap pathologically. The connections between α-Syn and tau led us to ask whether these proteins might be regulated through a shared pathway. We therefore screened for genes that affect post-translational levels of α-Syn and tau. We found that TRIM28 regulates α-Syn and tau levels and that its reduction rescues toxicity in animal models of tau- and α-Syn-mediated degeneration. TRIM28 stabilizes and promotes the nuclear accumulation and toxicity of both proteins. Intersecting screens across comorbid proteinopathies thus reveal shared mechanisms and therapeutic entry points.</p><p><bold>DOI:</bold><ext-link ext-link-type="doi" xlink:href="10.7554/eLife.19809.001">http://dx.doi.org/10.7554/eLife.19809.001</ext-link></p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Aleyasin, H" uniqKey="Aleyasin H">H Aleyasin</name></author><author><name sortKey="Rousseaux, Mwc" uniqKey="Rousseaux M">MWC Rousseaux</name></author><author><name sortKey="Phillips, M" uniqKey="Phillips M">M Phillips</name></author><author><name sortKey="Kim, Rh" uniqKey="Kim R">RH Kim</name></author><author><name sortKey="Bland, Rj" uniqKey="Bland R">RJ Bland</name></author><author><name sortKey="Callaghan, S" uniqKey="Callaghan S">S Callaghan</name></author><author><name sortKey="Slack, Rs" uniqKey="Slack R">RS Slack</name></author><author><name sortKey="During, Mj" uniqKey="During M">MJ During</name></author><author><name 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Lee</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country></list><tree><country name="États-Unis"><noRegion><name sortKey="Rousseaux, Maxime Wc" sort="Rousseaux, Maxime Wc" uniqKey="Rousseaux M" first="Maxime Wc" last="Rousseaux">Maxime Wc Rousseaux</name></noRegion><name sortKey="Al Ramahi, Ismael" sort="Al Ramahi, Ismael" uniqKey="Al Ramahi I" first="Ismael" last="Al-Ramahi">Ismael Al-Ramahi</name><name sortKey="Al Ramahi, Ismael" sort="Al Ramahi, Ismael" uniqKey="Al Ramahi I" first="Ismael" last="Al-Ramahi">Ismael Al-Ramahi</name><name sortKey="Botas, Juan" sort="Botas, Juan" uniqKey="Botas J" first="Juan" last="Botas">Juan Botas</name><name sortKey="Botas, Juan" sort="Botas, Juan" uniqKey="Botas J" first="Juan" last="Botas">Juan Botas</name><name sortKey="De Haro, Maria" sort="De Haro, Maria" uniqKey="De Haro M" first="Maria" last="De Haro">Maria De Haro</name><name sortKey="De Haro, Maria" 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Troncoso</name><name sortKey="Vilanova Velez, Luis" sort="Vilanova Velez, Luis" uniqKey="Vilanova Velez L" first="Luis" last="Vilanova-Velez">Luis Vilanova-Velez</name><name sortKey="Vilanova Velez, Luis" sort="Vilanova Velez, Luis" uniqKey="Vilanova Velez L" first="Luis" last="Vilanova-Velez">Luis Vilanova-Velez</name><name sortKey="Westbrook, Thomas F" sort="Westbrook, Thomas F" uniqKey="Westbrook T" first="Thomas F" last="Westbrook">Thomas F. Westbrook</name><name sortKey="Westbrook, Thomas F" sort="Westbrook, Thomas F" uniqKey="Westbrook T" first="Thomas F" last="Westbrook">Thomas F. Westbrook</name><name sortKey="Zoghbi, Huda Y" sort="Zoghbi, Huda Y" uniqKey="Zoghbi H" first="Huda Y" last="Zoghbi">Huda Y. Zoghbi</name><name sortKey="Zoghbi, Huda Y" sort="Zoghbi, Huda Y" uniqKey="Zoghbi H" first="Huda Y" last="Zoghbi">Huda Y. Zoghbi</name><name sortKey="Zoghbi, Huda Y" sort="Zoghbi, Huda Y" uniqKey="Zoghbi H" first="Huda Y" last="Zoghbi">Huda Y. Zoghbi</name></country><country name="Canada"><noRegion><name sortKey="De Maio, Antonia" sort="De Maio, Antonia" uniqKey="De Maio A" first="Antonia" last="De Maio">Antonia De Maio</name></noRegion><name sortKey="Zoghbi, Huda Y" sort="Zoghbi, Huda Y" uniqKey="Zoghbi H" first="Huda Y" last="Zoghbi">Huda Y. Zoghbi</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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