Proteomics Approach in the Study of the Pathophysiology of Alcohol-Related Brain Damage

Abstract

Chronic, excessive drinking of alcohol can induce brain damage in the regions important for neurocognitive function. Some of the damage are permanent while some are appearantly reversible. It is our aim to understand the molecular mechanisms underlying alcohol-induced and/or related brain damage, particularly of that observed in 'medically uncomplicated' (without heptatic cirrhosis or Wernicke-Korsakoff Syndrome [WKS]) alcoholics. A high-throughput proteomics technology has been applied to several 'alcohol-sensitive' brain regions from uncomplicated and hepatic cirrhosis-complicated alcoholics to understand the mechanisms of alcohol-related brain damage at the level of protein expression. It was clearly demonstrated that each brain region reacts in significantly different manner to chronic alcohol ingestion. Appearant abnormalities in vitamin B1 (thiamine)-related biochemical pathways were observed in several brain regions, such as the dorsolateral prefrontal cortex, genu (a frontal part of the corpus callosum) and cerebellar vermis in uncomplicated alcoholics, suggesting that the reduction of this important nutritional component might be associated with brain damage even without the signs of WKS. In addition, in the two different subregions of the corpus callosum (genu and splenium [a posterior part of the corpus callosum]) and the cerebellar vermis, significant differences in protein expression profiles between uncomplicated and complicated alcoholics with hepatic cirrhosis were identified, suggesting that hepatic factors such as ammonia have significant additive influences on brain protein expression, which might lead to the structural changes and/or damage in these brain regions. Furthermore, in the hippocampus, significant change of the level of glutamine synthetase expression was observed, suggesting once again the importance of ammonia as a cause of brain damage in this region. Although our data did not show any evidence of "direct" alcohol effects to induce the alteration of protein expression in association with brain damage, high-throughput neuroproteomics approaches are proven to have a potential to dissect the mechanisms of complex brain disorders.