title: Novel Therapeutic Targets and Drug Candidates for Modifying Disease Progression in Adrenoleukodystrophy.
abstract: X-linked adrenoleukodystrophy (X-ALD) is the most frequent inherited monogenic demyelinating disease. It is often lethal and currently lacks a satisfactory therapy. The disease is caused by loss of function of the ABCD1 gene, a peroxisomal ATP-binding cassette transporter, resulting in the accumulation of very-long-chain fatty acids (VLCFA) in organs and plasma. Recent findings on pathomechanisms of the peroxisomal neurometabolic disease X-ALD have provided important clues on therapeutic targets. Here we describe the impact of chronic redox imbalance caused by the excess VLCFA on mitochondrial biogenesis and respiration, and explore the consequences on the protein quality control systems essential for cell survival, such as the proteasome and autophagic flux. Defective proteostasis, together with mitochondrial malfunction, is a hallmark of the most prevalent neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, and of the aging process. Thus, we discuss molecular targets and emerging treatment options that may be common to both multifactorial neurodegenerative disorders and X-ALD. New-generation antioxidants, some of them mitochondrial targeted, mitochondrial biogenesis boosters such as pioglitazone and resveratrol, and the mTOR inhibitor temsirolimus hold promise as disease-modifying therapies.
authors.affiliation: Laboratory of Neurometabolic Diseases and Pathologic Anatomy Service, Institute of Neuropathology, Bellvitge Biomedical Research Institute (IDIBELL)-Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat and Center for Biomedical Research on Rare Diseases (CIBERER), U759, ISCIII, and Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain.
authors.forename: Aurora
authors.initials: A
authors.lastname: Pujol
mesh_terms: D000326:Adrenoleukodystrophy / Q000188:drug therapy* / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans