Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy.

Fox, Leora M; Kim, Kiryung; Johnson, Christopher W; Chen, Shawei; Croce, Katherine R; Victor, Matheus B; Eenjes, Evelien; Bosco, Joan R; Randolph, Lisa K; Dragatsis, Ioannis; Dragich, Joanna M; Yoo, Andrew S; Yamamoto, Ai

Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy.

Fox, Leora M; Kim, Kiryung; Johnson, Christopher W; Chen, Shawei; Croce, Katherine R; Victor, Matheus B; Eenjes, Evelien; Bosco, Joan R; Randolph, Lisa K; Dragatsis, Ioannis; Dragich, Joanna M; Yoo, Andrew S; Yamamoto, Ai.

Afiliación

Fox LM; Doctoral Program in Neurobiology and Behavior, Department of Neuroscience, Columbia University, New York, NY, USA; Department of Neurology, Columbia University, New York, NY, USA.
Kim K; Department of Neurology, Columbia University, New York, NY, USA.
Johnson CW; Department of Neurology, Columbia University, New York, NY, USA.
Chen S; Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Croce KR; Graduate Program in Pathobiology and Molecular Medicine, Columbia University, New York, NY, USA.
Victor MB; Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Eenjes E; Department of Neurology, Columbia University, New York, NY, USA.
Bosco JR; Department of Neurology, Columbia University, New York, NY, USA.
Randolph LK; Doctoral Program in Neurobiology and Behavior, Department of Neuroscience, Columbia University, New York, NY, USA.
Dragatsis I; Department of Physiology, University of Tennessee, Memphis, TN, USA.
Dragich JM; Department of Neurology, Columbia University, New York, NY, USA.
Yoo AS; Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Yamamoto A; Doctoral Program in Neurobiology and Behavior, Department of Neuroscience, Columbia University, New York, NY, USA; Department of Neurology, Columbia University, New York, NY, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. Electronic address: ai.yamamoto@columb

Neuron ; 105(5): 813-821.e6, 2020 03 04.

Article en En | MEDLINE | ID: mdl-31899071

RESUMEN

Despite being an autosomal dominant disorder caused by a known coding mutation in the gene HTT, Huntington's disease (HD) patients with similar trinucleotide repeat mutations can have an age of onset that varies by decades. One likely contributing factor is the genetic heterogeneity of patients that might modify their vulnerability to disease. We report that although the heterozygous depletion of the autophagy adaptor protein Alfy/Wdfy3 has no consequence in control mice, it significantly accelerates age of onset and progression of HD pathogenesis. Alfy is required in the adult brain for the autophagy-dependent clearance of proteinaceous deposits, and its depletion in mice and neurons derived from patient fibroblasts accelerates the aberrant accumulation of this pathological hallmark shared across adult-onset neurodegenerative diseases. These findings indicate that selectively compromising the ability to eliminate aggregated proteins is a pathogenic driver, and the selective elimination of aggregates may confer disease resistance.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/genética; Proteínas Relacionadas con la Autofagia/genética; Enfermedad de Huntington/genética; Macroautofagia/genética; Neuronas/metabolismo; Agregación Patológica de Proteínas/genética; Edad de Inicio; Animales; Muerte Celular/genética; Modelos Animales de Enfermedad; Femenino; Fibroblastos; Humanos; Proteína Huntingtina/genética; Proteína Huntingtina/metabolismo; Enfermedad de Huntington/metabolismo; Enfermedad de Huntington/fisiopatología; Masculino; Ratones; Ratones Noqueados; Agregación Patológica de Proteínas/metabolismo; Agregación Patológica de Proteínas/fisiopatología

Palabras clave

Alfy; Huntington's disease; Wdfy3; autophagy; direct conversion; mice; neurodegeneration; patient fibroblasts; proteinopathy; selective autophagy

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Huntington / Proteínas Adaptadoras Transductoras de Señales / Agregación Patológica de Proteínas / Proteínas Relacionadas con la Autofagia / Macroautofagia / Neuronas Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Female / Humans / Male Idioma: En Revista: Neuron Asunto de la revista: NEUROLOGIA Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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