Alcohol-related brain damage in humans.
Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA) 9) from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE) proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin β II, and α- and β-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in α-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in β-spectrin protein levels, and a significant increase in transmembranous α3 (catalytic) subunit of the Na+,K+-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of α-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic α- and β-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics.
School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom; Department of Pharmacology, University of the Basque Country, and Centro de Investigación Biomédica en Red de Salud Mental, Spain.
Amaia M
AM
Erdozain
Section of Forensic Pathology, Basque Institute of Legal Medicine, Bilbao, Spain.
Benito
B
Morentin
School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
Lynn
L
Bedford
School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
Emma
E
King
School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
David
D
Tooth
School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.
Charlotte
C
Brewer
School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.
Declan
D
Wayne
School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.
Laura
L
Johnson
School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.
Henry K
HK
Gerdes
School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, United Kingdom.
Peter
P
Wigmore
Department of Pharmacology, University of the Basque Country, and Centro de Investigación Biomédica en Red de Salud Mental, Spain.
Luis F
LF
Callado
School of Medicine, University of Nottingham, Royal Derby Hospital Centre, Derby, United Kingdom.
Wayne G
WG
Carter
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D009419:Nerve Tissue Proteins; D000431:Ethanol