Peroxisomal pathways, their role in neurodegenerative disorders and therapeutic strategies

X-linked adrenoleukodystrophy (X-ALD), the most frequent peroxisomal disease, is due to a mutation in the ABCD1 gene encoding for a protein important in the transport of acyl chains into peroxisomes for further oxidation. This leads to a defect in this transporter and to an accumulation of very long chain fatty acids (VLCFA), in particular of 26:0, in plasma and tissues, including brain. The high concentration of saturated VLCFA alters the structure and functions of cell membranes, and the toxic effects are attributable to the induction of oxidative stress and inflammation (also associated with autoimmune mechanisms). Dietary intervention and gene therapy have provided encouraging results, albeit with sometimes conflicting findings in different clinical studies. Elucidation of the molecular mechanisms associated with X-ALD should aid in developing new strategies, e.g. a synergistic approach acting on the different causes of the disease, and pharmacological therapies for X-ALD.