INVESTIGADORES
PIGINO Gustavo Fernando
artículos
Título:
JNK mediates pathogenic effects of polyglutamine-expanded androgen receptor on fast axonal transport.
Autor/es:
MORFINI G, PIGINO G, SZEBENYI G, YOU Y, POLLEMA S, BRADY ST.
Revista:
NATURE NEUROSCIENCE.
Editorial:
NATURE PUBLISHING GROUP
Referencias:
Lugar: Londres; Año: 2006 vol. 7 p. 907 - 916
ISSN:
1097-6256
Resumen:
Expansion of the polyglutamine (polyQ) stretch in the androgen receptor
(AR) protein leads to spinal and bulbar muscular atrophy (SBMA), a
neurodegenerative disease characterized by lower motor neuron
degeneration. The pathogenic mechanisms underlying SBMA remain unknown,
but recent experiments show that inhibition of fast axonal transport
(FAT) by polyQ-expanded proteins, including polyQ-AR, represents a new
cytoplasmic pathogenic lesion. Using pharmacological, biochemical and
cell biological experiments, we found a new pathogenic pathway that is
affected in SBMA and results in compromised FAT. PolyQ-AR inhibits FAT
in a human cell line and in squid axoplasm through a pathway that
involves activation of cJun N-terminal kinase (JNK) activity. Active JNK
phosphorylated kinesin-1 heavy chains and inhibited kinesin-1
microtubule-binding activity. JNK inhibitors prevented polyQ-AR-mediated
inhibition of FAT and reversed suppression of neurite formation by
polyQ-AR. We propose that JNK represents a promising target for
therapeutic interventions in SBMA.