DOI 10.1515/hsz-2012-0323 Biol. Chem. 2013; 394(5): 621–629 Minireview Jone López-Erauskin, Isidre Ferrer, Elena Galea a and Aurora Pujol a, * Cyclophilin D as a potential target for antioxidants in neurodegeneration: the X-ALD case Abstract: X-linked adrenoleukodystrophy (X-ALD) is a severe inherited neurodegenerative disorder character- ized by adrenal insufficiency and graded damage in the nervous system. Loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumula- tion of very long-chain fatty acids in organs and plasma, is the genetic cause. Treatment with a combination of antioxidants halts the axonal degeneration and locomo- tor impairment displayed by the animal model of X-ALD, and is a proof of concept that oxidative stress contributes to axonal damage. New evidence demonstrates that meta- bolic failure and the opening of the mitochondrial per- meability transition pore orchestrated by cyclophilin D underlies oxidative stress-induced axonal degeneration. Thus, cyclophilin D could serve as a therapeutic target for the treatment of X-ALD and cyclophilin D-dependent neu- rodegenerative and non-neurodegenerative diseases. Keywords: cyclophilin D; neurodegeneration; mitochon- drial permeability transition pore; oxidative stress; very long chain fatty acids; X-linked adrenoleukodystrophy. a These authors contributed equally to this work. *Corresponding author: Aurora Pujol, Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’ Hospitalet de Llobregat, E-08908 Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER) U759, L’ Hospitalet de Llobregat, E-08908 Barcelona, Spain; Institute of Neuropathology, Pathologic Anatomy Service, Bellvitge Biomedical Research Institute, IDIBELL-Hospital Universitari de Bellvitge, L’ Hospitalet de Llobregat, E-08908 Barcelona, Spain; and Catalan Institution of Research and Advanced Studies (ICREA), E-08010 Barcelona, Spain, e-mail: apujol@idibell.cat Jone López-Erauskin: Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’ Hospitalet de Llobregat, E-08908 Barcelona, Spain; Center for Biomedical Research on Rare Diseases (CIBERER) U759, L’ Hospitalet de Llobregat, E-08908 Barcelona, Spain; and Institute of Neuropathology, Pathologic Anatomy Service, Bellvitge Biomedical Research Institute, IDIBELL-Hospital Universitari de Bellvitge, L’ Hospitalet de Llobregat, E-08908 Barcelona, Spain Isidre Ferrer: Institute of Neuropathology, Pathologic Anatomy Service, Bellvitge Biomedical Research Institute, IDIBELL- Hospital Universitari de Bellvitge, L’ Hospitalet de Llobregat, E-08908 Barcelona, Spain; and Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), L’ Hospitalet de Llobregat, E-08908 Barcelona, Spain Elena Galea: Institute of Neuroscience, Universitat Autònoma de Barcelona, E-08193 Barcelona, Spain; and Catalan Institution of Research and Advanced Studies (ICREA), E-08010 Barcelona, Spain Introduction: general features of X-linked adrenoleukodystrophy and animal models of the disease X-linked adrenoleukodystrophy (X-ALD: McKusick no. 300100) is a rare neurometabolic disease character- ized by progressive demyelination within the central nervous system (CNS), axonopathy in the spinal cord, and adrenal insufficiency. This inheritable disorder is caused by mutations in the ABCD1 (ALD) gene located in Xq28. This encodes for the peroxisomal ABCD (ALD protein) transporter (Mosser et al., 1993), which is involved in importing very long-chain fatty acids (VLCFAs) and very long-chain fatty acid–Coenzyme A (VLCFA–CoA) esters into the peroxisome, where they are degraded by β-oxidation (Singh et al., 1984; Wanders et al., 1987; van Roermund et al., 2008; Fourcade et al., 2009). Defective function of the ABCD1 transporter leads to VLCFA accu- mulation in most organs and plasma, and elevated levels of VLCFAs are used as a biomarker for the biochemical diagnosis of the disease (Berger and Gartner , 2006; Moser et al., 2007). X-ALD is the most common monogenic leu- kodystrophy and peroxisomal disorder, occurring in at least 1 out of 16 800 people (Bezman et al., 2001). Four major disease variants have been described: – Adrenomyeloneuropathy (AMN), a late-onset form presenting a slow progression and characterized by a peripheral neuropathy and distal axonopathy in the spinal cord. This phenotype is often, but not always, associated with axonal or demyelinating peripheral neuropathy and can affect both adult men and women. Brought to you by | UNAM Authenticated | 132.248.107.131 Download Date | 4/3/13 1:29 AM