Abstract
In X-ALD, mutation/deletion of ALD gene (ABCD1) and the resultant very long chain fatty acid (VLCFA) derangement has dramatically opposing effects in astrocytes and oligodendrocytes. While loss of Abcd1 in astrocytes produces a robust inflammatory response, the oligodendrocytes undergo cell death leading to demyelination in X-linked adrenoleukodystrophy (X-ALD). The mechanisms of these distinct pathways in the two cell types are not well understood. Here, we investigated the effects of Abcd1-knockdown and the subsequent alteration in VLCFA metabolism in human U87 astrocytes and rat B12 oligodendrocytes. Loss of Abcd1 inhibited peroxisomal β-oxidation activity and increased expression of VLCFA synthesizing enzymes, elongase of very long chain fatty acids (ELOVLs) (1 and 3) in both cell types. However, higher induction of ELOVL's in Abcd1-deficient B12 oligodendrocytes than astrocytes suggests that ELOVL pathway may play a prominent role in oligodendrocytes in X-ALD. While astrocytes are able to maintain the cellular homeostasis of anti-apoptotic proteins, Abcd1-deletion in B12 oligodendrocytes downregulated the anti-apototic (Bcl-2 and Bcl-xL) and cell survival (phospho-Erk1/2) proteins, and upregulated the pro-apoptotic proteins (Bad, Bim, Bax and Bid) leading to cell loss. These observations provide insights into different cellular signaling mechanisms in response to Abcd1-deletion in two different cell types of CNS. The apoptotic responses were accompanied by activation of caspase-3 and caspase-9 suggesting the involvement of mitochondrial-caspase-9-dependent mechanism in Abcd1-deficient oligodendrocytes. Treatment with histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) corrected the VLCFA derangement both in vitro and in vivo, and inhibited the oligodendrocytes loss. These observations provide a proof-of principle that HDAC inhibitor SAHA may have a therapeutic potential for X-ALD.
Highlights
The ALD gene (ABCD1), identified by positional cloning [1], encodes a protein ALDP that is related to the peroxisomal ATPbinding cassette (ABCD) transmembrane transporter proteins [2,3]
Using U87 astrocytes and B12 oligodendrocytes stably silenced for Abcd1 using lentiviral vectors, this study describes the astrocyte vs. oligodendrocyte-specific very long chain fatty acids (VLCFA)-mediated derangements and activation of mitochondrial cell death pathways
Since overexpression of Abcd2 and Abcd3 can compensate for loss of Abcd1 [34,35], we investigated the effect of Abcd1 silencing on the expression of Abcd2 and Abcd3 in U87 astrocytes and B12 oligodendrocytes
Summary
The ALD gene (ABCD1), identified by positional cloning [1], encodes a protein ALDP that is related to the peroxisomal ATPbinding cassette (ABCD) transmembrane transporter proteins [2,3]. Loss of ABCD1 function results in defective b-oxidation of very long chain fatty acids (VLCFA) [4] resulting in accumulation of VLCFA, the biochemical ‘‘hallmark’’ of X-ALD, in plasma and tissues, most notably in brain and adrenal cortex [5]. Recent studies from our laboratory [6,7] and others [8] show a correlation between VLCFA accumulation caused by silencing of peroxisomal transporters in neural tissue in X-ALD and glial cells to redox imbalance, and changes in membrane lipid composition [6,7,9,10,11] leading to astrocytic inflammatory response and loss of oligodendrocytes and myelin [10,12]. In XALD CNS, altered activities of ELOVLs and peroxisomal b-oxidation as well as the secondary effects of inflammatory mediators may contribute towards the observed pathognomic levels of VLCFA. Abcd1-KO mice treated with SAHA in diet had significantly lower VLCFA levels in the brain providing the first pre-clinical proof-of-principal for testing SAHA as therapy for X-ALD
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