Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathy

• Tipo: Artigo em Revista Científica Internacional
• Data: 2006

Autores

Filipe Monteiro (Autor) Outra; Monica M Sousa (Autor) ICBAS; Cardoso, I (Autor) Outra; do Amaral, JB (Autor) Outra; Guimaraes, A (Autor) Outra; Maria Joao Saraiva (Autor) ICBAS

Revista

Título: Journal of Neurochemistry

Vol. 97

Páginas: 151-161

ISSN: 0022-3042

Editora: Wiley-Blackwell

Indexação

ISI Web of Knowledge - 46 Citações

Scopus - 51 Citações

Outras Informações

ID Authenticus: P-004-MGP

DOI: 10.1111/j.1471-4159.2006.03716.x

Abstract (EN): Familial amyloidotic polyneuropathy (FAP) is a neurodegenerative disorder characterized by the extracellular deposition of transthyretin (TTR), especially in the PNS. Given the invasiveness of nerve biopsy, salivary glands (SG) from FAP patients were used previously in microarray analysis; mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) was down-regulated in FAP. Results were validated by RT-PCR and immunohistochemistry both in SG and in nerve biopsies of different stages of disease progression. MKP-3 was also down-regulated in FAP SG biopsies. Given the relationship between MKPs and MAPKs, the latter were investigated. Only extracellular signal-regulated kinases 1/2 (ERK1/2) displayed increased activation in FAP SG and nerves. ERK1/2 kinase (MEK1/2) activation was also up-regulated in FAP nerves. In addition, an FAP transgenic mouse model revealed increased ERK1/2 activation in peripheral nerve affected with TTR deposition when compared to control animals. Cultured rat Schwannoma cell line treatment with TTR aggregates stimulated ERK1/2 activation, which was partially mediated by the receptor for advanced glycation end-products (RAGE). Moreover, caspase-3 activation triggered by TTR aggregates was abrogated by U0126, a MEK1/2 inhibitor, indicating that ERK1/2 activation is essential for TTR aggregates-induced cytotoxicity. Taken together, these data suggest that abnormally sustained activation of ERK in FAP may represent an early signaling cascade leading to neurodegeneration.

Idioma: Inglês

Tipo (Avaliação Docente): Científica

Nº de páginas: 11