Pharmacological Research 52 (2005) 140–150 Prevention of cytosolic IAPs degradation: a potential pharmacological target in Huntington’s Disease Donato Goffredo 1 , Dorotea Rigamonti 1 , Chiara Zuccato 1 , Marzia Tartari, Marta Valenza, Elena Cattaneo ∗ Department of Pharmacological Sciences and Center of Excellence on Neurodegenerative Diseases, University of Milano, Via Balzaretti 9, 20133 Milano, Italy Accepted 21 January 2005 Abstract Huntington’s Disease (HD) is a neurodegenerative disorder caused by an abnormally expanded polyglutamine trait in the amino-terminal region of huntingtin. Pathogenic mechanisms involve a gained toxicity of mutant huntingtin and a potentially reduced neuroprotective function of the wild-type allele. Among the molecular abnormalities reported, HD cells are characterized by the presence of aggregates, transcriptional dysregulation, altered mitochondrial membrane potential and aberrant Ca++ handling. In addition, upon exposure to toxic stimuli, increased mitochondrial release of cytochrome C and activation of caspase-9 and caspase-3 are found in HD cells and tissue. Here we report that HTRA2 and Smac/DIABLO, two additional mitochondrial pro-apoptotic factors, are aberrantly released from brain- derived cells expressing mutant huntingtin. This event causes a reduction in levels of the cytosolic IAP1 (Inhibitor of Apoptosis Protein-1) and XIAP (X-linked inhibitor apoptosis) antiapoptotic IAP family members. Reduced IAP levels are also found in post-mortem HD brain tissue. Treatment with ucf101, a serine protease HTRA2 specific inhibitor, counteracts IAPs degradation in HD cells and increases their survival. These results point to the IAPs as potential pharmacological targets in Huntington’s Disease. © 2005 Elsevier Ltd. All rights reserved. Keywords: Huntington’s disease; IAP; HTRA2; Smac/DIABLO; Mitochondria 1. Introduction Huntington’s Disease belongs to a group of inherited neu- rodegenerative polyglutamine diseases, so called since they are all characterised by the death of different classes of neu- rons due to the presence of an expanded polyglutamine trait in different proteins [1]. In the case of HD, the disease- causing protein, named huntingtin, bears an amino-terminal glutamine sequence that becomes elongated to more than 36 glutamine and leading to the loss of striatal and cortical neu- rons [2]. There is evidence which suggests that this muta- tion causes both a gained toxic activity of the mutant protein ∗ Corresponding author. Tel.: +39 02 50318333/349; fax: +39 02 50318284. E-mail address: elena.cattaneo@unimi.it (E. Cattaneo). 1 Co-first authors. and the loss of normal huntingtin function [3]. Normal hunt- ingtin is antiapoptotic for brain cells both in vitro [4,5] and in vivo [6]. In addition, wild-type huntingtin promotes BDNF production and favors the transcription of Neuron Restric- tive Silencer Element (NRSE) controlling neuronal genes [7–9]. Huntingtin also has a role during embryogenesis as suggested by the observed lethality of knock-out mouse em- bryo [10–13]. Mitochondria have an important function in the neu- ropathological events occurring in HD striatal neurons [14,15]. The mitochondrial abnormalities consist of two main deficits. The first involves a deficit in energy metabolism, as demonstrated by a diminished ATP production due to de- fects in complex II and III mitochondrial respiratory chain activity. The second involves increased susceptibility to de- polarization. In fact, lymphoblasts from HD subjects are more susceptible to apoptotic stress-induced mitochondrial 1043-6618/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2005.01.006