X-linked Adrenoleukodystrophy: Metabolic Defect And Pharmacological Therapy

X-linked adrenoleukodystrophy(X-ALD) is the most common peroxisomal disorder, associated with elevated levels of saturated unbranched very long chain fatty acid(VLCFA;C>22:0) and reduced VLCFA β oxidation in plasma and tissues. Clinical manifestations of X-ALD are highly variable with respect to age of onset, rate of progression, and site of initial neurological involvement. The X-ALD gene at Xq28 encodes the adrenoleukodystrophy protein (ALDP) that is related to the peroxisomal ATP Binding Cassette (ABC) transmemberane half-transporter protein. The function of ALDP is unknown and its role in VLCFA accumulation is unresolved.There are several indications that oxidative stress is likely to play a role in pathophysiology of X-ALD. In this study, immunohistochemical studies showed that MnSOD protein was increased in the brain of X-ALD mouse, immunofluorescent studies showed that there is more detectable MnSOD protein in fibroblasts from X-ALD patients, quantitative PCR showed that MnSOD mRNA is increased in fibroblasts from CCER (one form of X-ALD) patients. These are the first observations that X-ALD is associated with oxidative stress.Enhanced expression of genes involved in metabolic pathways or peroxisome proliferation by drug treatment may be helpful for VLCFA decomposition and inner-cellular environment amelioration, and thus may be approaches to therapy of X-ALD. In this study we tried to induce the expression of MnSOD, ALDR, PPAR α, PPAR γ and Pexll α by 4PBA, 3PBA and TSA, and observed that expression of MnSOD, PPAR α and PeXll α can be induced by one or two drugs (4PBA and/or 3PBA) . Those genes may be candidates of pharmacological gene therapy.These studies contribute to a better understanding of the metabolic defect of X-ALD and may lead to the development of more effective pharmacological therapies.