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Peripheral sequestration of huntingtin delays neuronal death and depends on N-terminal ubiquitination.
Boulos, Ayub; Maroun, Dunia; Ciechanover, Aaron; Ziv, Noam E.
Afiliación
  • Boulos A; Technion Faculty of Medicine, Rappaport Institute and Network Biology Research Laboratories, Fishbach Building, Technion City, Haifa, Israel.
  • Maroun D; Department of Neurology, Massachusetts General Hospital, and Harvard Medical School, Charlestown, MA, USA.
  • Ciechanover A; Technion Faculty of Medicine, Rappaport Institute and Network Biology Research Laboratories, Fishbach Building, Technion City, Haifa, Israel.
  • Ziv NE; Rappaport Faculty of Medicine and Rappaport Technion Integrated Cancer Center (RTICC), Technion-Israel Institute of Technology, Haifa, Israel.
Commun Biol ; 7(1): 1014, 2024 Aug 18.
Article en En | MEDLINE | ID: mdl-39155290
ABSTRACT
Huntington's disease (HD) is caused by a glutamine repeat expansion in the protein huntingtin. Mutated huntingtin (mHtt) forms aggregates whose impacts on neuronal survival are still debated. Using weeks-long, continual imaging of cortical neurons, we find that mHtt is gradually sequestrated into peripheral, mainly axonal aggregates, concomitant with dramatic reductions in cytosolic mHtt levels and enhanced neuronal survival. in-situ pulse-chase imaging reveals that aggregates continually gain and lose mHtt, in line with these acting as mHtt sinks at equilibrium with cytosolic pools. Mutating two N-terminal lysines found to be ubiquitinated in HD animal models suppresses peripheral aggregate formation and reductions in cytosolic mHtt, promotes nuclear aggregate formation, stabilizes aggregates and leads to pervasive neuronal death. These findings demonstrate the capacity of aggregates formed at peripheral locations to sequester away cytosolic, presumably toxic mHtt forms and support a crucial role for N-terminal ubiquitination in promoting these processes and delaying neuronal death.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Muerte Celular / Enfermedad de Huntington / Ubiquitinación / Proteína Huntingtina / Neuronas Límite: Animals / Humans Idioma: En Revista: Commun Biol Año: 2024 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Muerte Celular / Enfermedad de Huntington / Ubiquitinación / Proteína Huntingtina / Neuronas Límite: Animals / Humans Idioma: En Revista: Commun Biol Año: 2024 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Reino Unido