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Notes:
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Oxidative injury and stress responses are common features of
many neurodegenerative diseases. To assess oxidative stress responses
in frontotemporal lobar degeneration (FTLD), we identified
increased 4-hydroxynonenal (HNE) adducts using gel electrophoresis
and Western blotting in frontal cortex samples in 6 of 6 cases of
FTLD with the P301L mutation in the tau gene (FTLD-tau), in 3 of
10 cases with tau-negative ubiquitin-immunoreactive inclusions, and
in 2 of 3 cases associated with motor neuron disease. Selectively
increased lipoxidation-derived protein damage associated with altered
membrane unsaturation and fatty acid profiles was verified by
mass spectrometry in FTLD-tau and FTLD associated with motor
neuron disease. All FTLD-tau and most cases with increased HNEpositive
bands had marked astrocytosis as determined by glial
fibrillary acidic protein (GFAP) immunohistochemistry and
increased GFAP expression on Western blotting; 2 FTLD cases with
tau-negative ubiquitin-immunoreactive inclusions and with increased
GFAP expression did not have increased HNE adducts. Bidimensional
gel electrophoresis, Western blotting, in-gel digestion, and
mass spectrometry identified GFAP as a major target of lipoxidation
in all positive cases; confocal microscopy revealed colocalization of
HNE and GFAP in cortical astrocytes, superoxide dismutase 1 in
astrocytes, and superoxide dismutase 2 in astrocytes and neurons in
all FTLD types. Thus, in FTLD, there is variable disease-dependent
oxidative damage that is prominent in FTLD-tau, astrocytes are
targets of oxidative damage, and GFAP is a target of lipoxidation.
Astrocytes are, therefore, crucial elements of oxidative stress
responses in FTLD.
This work was supported by Grants PI05/1570 and PI05/2214 from the Spanish Ministry of Health, Instituto de Salud Carlos III, and by Grant LSHM-CT-2004-503039 from the European Commission under the Sixth Framework Program (BrainNet Europe II) to Isidre Ferrer; by Grant BFU2006-14495/BFI from the Spanish Ministry of Education and Science, by Grant RD06/0013/0012 from the Spanish Ministry of Health (ISCIII, Red de Envejecimiento y Fragilidad), and by Grant 2005SGR00101 from the Autonomous Government of Catalonia to Reinald Pamplona; and by the Spanish Ministry of Health (Grants PI04/0355, PI05/2214, and PI05/2241), Spanish Ministry of Education and Science (Grant AGL2006-12433), B La Caixa[ Foundation, and COST B-35 Action to Manuel Portero-Otin. |
