Huntington's Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy.
Neuron
; 105(5): 813-821.e6, 2020 03 04.
Article
em En
| MEDLINE
| ID: mdl-31899071
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Doença de Huntington
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Proteínas Adaptadoras de Transdução de Sinal
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Agregação Patológica de Proteínas
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Proteínas Relacionadas à Autofagia
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Macroautofagia
/
Neurônios
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Neuron
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos