Herp mRNA expression in patients classified according to Lesch’s typology T. Biermann * ,y , U. Reulbach y , B. Lenz, M. Muschler, W. Sperling, T. Hillemacher, J. Kornhuber, S. Bleich a Department of Psychiatry and Psychotherapy, University Hospital of Erlangen, Schwabachanlage 6, D-91054 Erlangen, Germany Received 17 June 2008; accepted 30 December 2008 Abstract Chronic alcoholism is associated with hyperhomocysteinemia. Herp (homocysteine-induced endoplasmic reticulum [ER] protein) levels are elevated as a response to ER stress prior to mitochondrial dysfunction and cell death. The Lesch classification system has been applied in many studies and has been found useful. This study was undertaken to assess Herp mRNA expression in actively drinking patients with alcoholism who were classified according to Lesch’s typology. Herp mRNA expression levels were measured by quantitative PCR in the blood of 76 male alcoholic patients. Patients were classified according to Lesch’s typology (type IeIV). With respect to Lesch’s typology, a significant difference in Herp mRNA expression regarding the four subtypes could be shown (F[3,72] 5 2.83, P 5 .044). In a logistic regression model (dependent variable Herp dichotomized by a median-split; adjusted for age and homocysteine levels) the subtype II differed statistically significant from the others (odds ratio, 5.75; 95% confidence interval, 2.07e15.98; P 5 .001). Type II alcoholic patients had a statistically significant higher expression of Herp mRNA due to upregulation of the expression of this neuroprotective cell non-chap- erone by toxic effects of ethanol. These findings might explain why type II patients do not express severe withdrawal symptomatology (i.e., withdrawal seizures). These findings may be useful in the understanding and treatment considerations of different subtypes of alcohol dependence. Ó 2009 Elsevier Inc. All rights reserved. Keywords: Lesch’s classification; Herp; mRNA; Alcoholism Introduction Chronic alcoholism, especially in non-abstinent subjects, is associated with hyperhomocysteinemia (Bleich et al., 2000a, 2000b, 2005). This substantial association between alcohol dependence and elevated plasma homocysteine contributes to different pathophysiologic consequences of alcoholism, such as brain atrophy (Bleich et al., 2003), alcohol withdrawal seizures (Bayerlein et al., 2005; Bleich et al., 2001, 2006a, 2006b), or short-term cognitive deficits during the clinical relevant withdrawal syndrome (Wilhelm et al., 2005). The endoplasmic reticulum (ER) belongs to the main target areas of intracellular homocysteine toxicity (Kokame et al., 1996; Mattson and Shea, 2003). Under conditions of stress, misfolded proteins accumulate in the ER lumen (Althausen and Paschen, 2000), homocysteine elevates the expression of both ER chaperone proteins (e.g., grp78, grp94, gadd153; Nonaka et al., 2001; Outinen et al., 1998), and the homocysteine-induced unfolded non-chaperone Herp (homocysteine-induced ER protein) in neuronal cells (Bleich et al., 2006a, 2006b; Kokame et al., 2000). Herp is an ER-resident membrane protein with an ubiquitin-like domain at its N-terminus and is present in neurons of the developing and the adult brain. Herp protein levels are elevated as a response to lethal ER stress prior to mitochon- drial dysfunction and cell death, including homocysteine (Hori et al., 2004; Kokame et al., 2000). Herp appears to play a pivotal role in regulating neuronal Ca 2þ signaling (Chan et al., 2004). Intracellular Ca 2þ overload is known to induce mitochondrial damage, thereby causing neurotoxicity (Schinder et al., 1996). In patients with alcoholism, a signifi- cant increase in gene-specific DNA methylation within the Herp promoter can be found, which is correlated positively to elevated homocysteine levels, whereas Herp mRNA expression is found to be lower compared to healthy controls (Bleich et al., 2006a, 2006b; Lenz et al., 2006). * Corresponding author. Tel.: þ49-9131-85-44773; fax: þ49-9131-85- 34105. E-mail address: teresa.biermann@uk-erlangen.de (T. Biermann). y Each author contributed equally. 0741-8329/09/$ e see front matter Ó 2009 Elsevier Inc. All rights reserved. doi: 10.1016/j.alcohol.2008.12.008 Alcohol 43 (2009) 91e95