A human huntingtin SNP alters post-translational modification and pathogenic proteolysis of the protein causing Huntington disease.
Sci Rep
; 8(1): 8096, 2018 05 25.
Article
em En
| MEDLINE
| ID: mdl-29802276
ABSTRACT
Post-translational modifications (PTMs) are key modulators of protein function. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene. A spectrum of PTMs have been shown to modify the normal functions of HTT, including proteolysis, phosphorylation and lipidation, but the full contribution of these PTMs to the molecular pathogenesis of HD remains unclear. In this study, we examine all commonly occurring missense mutations in HTT to identify potential human modifiers of HTT PTMs relevant to HD biology. We reveal a SNP that modifies post-translational myristoylation of HTT, resulting in downstream alterations to toxic HTT proteolysis in human cells. This is the first SNP shown to functionally modify a PTM in HD and the first validated genetic modifier of post-translational myristoylation. This SNP is a high-priority candidate modifier of HD phenotypes and may illuminate HD biology in human studies.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Processamento de Proteína Pós-Traducional
/
Doença de Huntington
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Polimorfismo de Nucleotídeo Único
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Proteólise
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Proteína Huntingtina
Limite:
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article