1. ¹Department of Neurology and Laboratory of Neuroscience, 'Dino Ferrari' Center, University of Milan Medical School, IRCCS Istituto Auxologico Italiano, Milan, Italy
2. ²Unit of Metabolic Diseases and Diabetes, IRCCS Istituto Auxologico Italiano, Milan, Italy
3. ³Department of Neurology, University of Milan Medical School, San Donato Hospital, San Donato, Italy
4. ⁴Department of Biomolecular Sciences and Biotechnologies, University of Milan, Milan, Italy
5. ⁵Department of Experimental Medicine and Pathology, University 'La Sapienza', Rome, Italy
6. ⁶IRCCS San Raffaele La Pisana, Rome, Italy
7. ⁷Neurogenetics Unit and Centre for Rare Diseases, IRCCS Neuromed, Pozzilli (IS), Italy
8. ⁸These authors contributed equally to this work.

Correspondence: A Ciammola, Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, via Spagnoletto 3, 20149, Milan, Italy. Tel: +39 02-619112937; Fax: +39 02-619112937; E-mail: a.ciammola@auxologico.it; F Squitieri, Neurogenetics Unit and Centre for Rare Diseases, IRCCS Neuromed, Localita' Camerelle, 86077, Pozzilli (IS), Italy. Tel.: +39 0865 915238; Fax: +39 0865 927575; E-mail: neurogen@neuromed.it

Received 8 August 2005; Revised 27 March 2006; Accepted 11 April 2006; Published online 26 May 2006.

Abstract

Mutated huntingtin (htt) is ubiquitously expressed in tissues of Huntington's disease (HD) patients. In the brain, the mutated protein leads to neuronal cell dysfunction and death, associated with formation of htt-positive inclusions. Given increasing evidence of abnormalities in HD skeletal muscle, we extensively analyzed primary muscle cell cultures from seven HD subjects (including two unaffected mutation carriers). Myoblasts from presymptomatic and symptomatic HD subjects showed cellular abnormalities in vitro, namely mitochondrial depolarization, cytochrome c release, increased caspase-3, -8, and -9 activities, and defective cell differentiation. Another notable feature was the formation of htt inclusions in differentiated myotubes. This study helps to advance current knowledge about the downstream effects of the htt mutation in human tissues. Further applications may include drug screening using this human cellular model.