Andersson S, Gustafsson N, Warner M, Gustafsson JA. Inactivation of liver X receptor beta leads to adult-onset motor neuron degeneration in male mice. Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3857-62. PubMed.
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Boston University School of Medicine
Increasing attention has been focused on the role of LXR in neurodegeneration. LXR is a transcription factor whose activity is
controlled by the class of cholesterol catabolites termed oxysterols.
LXR regulates many genes relevant to lipid metabolism including ApoE,
ABCA1 and LRP. Prior studies from the same group demonstrated that
knockout of LXR produced changes in lipid metabolism in the brain,
including modest accumulation of cholesterol, and a small amount of
neurodegeneration. The recent article by Andersson and colleagues
presents a more robust neurodegenerative effect that shows some aspects
similar to ALS. If LXR contributes to or modifies ALS pathophysiology,
this opens up new avenues of investigation for pharmacotherapy of the
disease.
Georgetown University
LXR¹s are nuclear hormone receptors that bind to hydroxylated forms of cholesterol and promote transcription of genes involved in lipid homeostasis (e.g., ApoE, ABCA1). Cholesterol homeostasis is poorly understood in the brain, but of obvious importance because of the high cholesterol content (25 percent of total body cholesterol, mostly in myelin). This importance is again emphasized by this recent publication of Andersson et al., who found that deletion of LXRβ (the form of LXR found in brain) in mice resulted in lipid accumulation and neuronal loss at seven months (but not at three months). What is particularly fascinating is that there was a selective vulnerability of the large motor neurons in the male mice, leading to impaired performance on rota-rod tests. The authors point out that this is reminiscent of ALS patients. Selective vulnerability of classes of neurons is a major enigma in neurodegenerative diseases. It would be interesting to examine whether there are other links between impaired cholesterol efflux and motor neuron diseases.
The brain is thought to make most, perhaps all, of its cholesterol. After brain damages, there is an excess of cholesterol and lipids in the brain, as neurons die and as myelin disappears. These processes likely involve LXRβ-induced genes, and the exported lipids could then be removed from the brain, or delivered to other cells that could use them (e.g., surviving neurons that are growing new processes). The Andersson et al. study suggests that even under normal conditions, regulation of cholesterol homeostasis is important for maintaining neuronal survival.
Lilly Research Laboratories
Liver X Receptors and Neurodegenerative Diseases
A growing body of literature suggests that cholesterol plays a central role in multiple neurodegenerative diseases. This paper provides further evidence for the importance of cholesterol following the original studies in LXRα and LXRβ double knockout mice. The phenotypes reminiscent of amyotrophic lateral sclerosis (ALS) in male LXRβ-deficient mice were closely associated with increased lipid deposition in spinal cord and loss of motor neurons.
It is not yet clear that increased lipid accumulation in spinal cord per se is the underlying cause for the observed phenotypes, although it is known that LXRs are master transcription factors mediating cholesterol catabolism. The most recent findings from CYP46A1-deficient mice with learning and memory defects (David Russell, 2005 Deuel Lipid Conference) clearly suggest the importance of proper cholesterol turnover in these processes. LXRβ is predominantly expressed in peripheral tissues but also the brain and has been implicated in anti-inflammatory process as well as in protection of macrophage apoptosis. Further studies will be needed to establish the potential mechanism leading to the reported observations with LXRβ deficiency. Additionally, the use of LXR agonists that effectively modulate cholesterol efflux and anti-inflammatory processes should be investigated for the potential treatment of neurodegenerative disorders, such as ALS and AD.
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