Proteolytic Cleavage of Polyglutamine Disease-Causing Proteins: Revisiting the Toxic Fragment Hypothesis

• Tipo: Outra Publicação em Revista Científica Internacional
• Data: 2017

Autores

Matos, CA (Autor) Outra; de Almeida, LP (Autor) Outra; Nobrega, C (Autor) Outra

Revista

Título: Current Pharmaceutical Design

Vol. 23

Páginas: 753-775

ISSN: 1381-6128

Editora: Bentham Science

Indexação

ISI Web of Knowledge - 20 Citações

Scopus - 29 Citações

Outras Informações

ID Authenticus: P-00M-SG2

DOI: 10.2174/1381612822666161227121912

Abstract (EN): Proteolytic cleavage has been implicated in the pathogenesis of diverse neurodegenerative diseases involving abnormal protein accumulation. Polyglutamine diseases are a group of nine hereditary disorders caused by an abnormal expansion of repeated glutamine tracts contained in otherwise unrelated proteins. When expanded, these proteins display toxic properties and are prone to aggregate, but the mechanisms responsible for the selective neurodegeneration observed in polyglutamine disease patients are still poorly understood. It has been suggested that the neuronal toxicity of polyglutamine-expanded proteins is associated with the production of deleterious protein fragments. This review aims at discussing the involvement of proteolytic cleavage in the six types of spinocerebellar ataxia caused by polyglutamine expansion of proteins. The analysis takes into detailed consideration evidence concerning fragment detection and the mechanisms of fragment toxicity. Current evidence suggests that the proteins involved in spinocerebellar ataxia types 3, 6 and 7 give rise to stable proteolytic fragments. Fragments carrying polyglutamine expansions display increased tendency to aggregate and toxicity, comparing with their non-expanded counterparts or with the correspondent full-length expanded proteins. Data concerning spinocerebellar ataxia types 1, 2 and 17 is still scarce, but available results afford further investigation. Available literature suggests that proteolytic cleavage of expanded polyglutamine-containing proteins enhances toxicity in disease-associated contexts and may constitute an important step in the pathogenic cascade of polyglutamine diseases. Countering protein fragmentation thus presents itself as a promising therapeutic aim.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 23