INVESTIGADORES
PIGINO Gustavo Fernando
artículos
Título:
Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta.
Autor/es:
PIGINO G, MORFINI G, ATAGI Y, DESHPANDE A, YU C, JUNGBAUER L, LADU M, BUSCIGLIO J, BRADY S.
Revista:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Editorial:
NATL ACAD SCIENCES
Referencias:
Lugar: Washington DC, USA; Año: 2009 vol. 106 p. 5907 - 5912
ISSN:
0027-8424
Resumen:
The pathological mechanism by which Abeta causes neuronal dysfunction
and death remains largely unknown. Deficiencies in fast axonal transport
(FAT) were suggested to play a crucial role in neuronal dysfunction and
loss for a diverse set of dying back neuropathologies including
Alzheimer's disease (AD), but the molecular basis for pathological
changes in FAT were undetermined. Recent findings indicate that soluble
intracellular oligomeric Abeta (oAbeta) species may play a critical role
in AD pathology. Real-time analysis of vesicle mobility in isolated
axoplasms perfused with oAbeta showed bidirectional axonal transport
inhibition as a consequence of endogenous casein kinase 2 (CK2)
activation. Conversely, neither unaggregated amyloid beta nor fibrillar
amyloid beta affected FAT. Inhibition of FAT by oAbeta was prevented by
two specific pharmacological inhibitors of CK2, as well as by
competition with a CK2 substrate peptide. Furthermore, perfusion of
axoplasms with active CK2 mimics the inhibitory effects of oAbeta on
FAT. Both oAbeta and CK2 treatment of axoplasm led to increased
phosphorylation of kinesin-1 light chains and subsequent release of
kinesin from its cargoes. Therefore pharmacological modulation of CK2
activity may represent a promising target for therapeutic intervention
in AD.