Kim HJ, Fan X, Gabbi C, Yakimchuk K, Parini P, Warner M, Gustafsson JA. Liver X receptor beta (LXRbeta): a link between beta-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2094-9. PubMed.

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  1. The remarkably high incidence of ALS among the Chamorros of Guam in the mid-1940s, and the characterization of a related neurodegenerative disorder, Parkinson-dementia complex (PDC), have never been adequately explained. Patterns of disease within families raise the possibility of genetic susceptibility, whereas the rapid decline of ALS on Guam following rapid Westernization of the island after World War II suggests an environmental factor. Preparing food from the seeds of cycad plants was thought to be a risk factor, but direct evidence has been lacking or controversial (Miller, 2006).

    We have recently found that reported eating of cycads during young adulthood was a risk factor for PDC or dementia in Chamorros (Galasko et al., 2007), and that polymorphisms in the tau gene are associated with increased risk of ALS, PDC, and dementia (Sundar et al., 2007). Although animal experiments have shown variable or no toxicity after feeding with various cycad preparations, Chris Shaw and associates found that feeding with a cycad sterol glucoside led to motor impairment in mice (Khabazian et al., 2002; Wilson et al., 2002).

    Gustafsson et al. in this paper have now integrated toxicity with genetic susceptibility by feeding transgenic mice deficient in the liver X receptor β (which is expressed in the brain) a plant sterol known to be potentially neurotoxic (β-sitosterol). Neurotoxicity was accelerated when feeding began at 5 months or older. It included motor neuron loss in the spinal cord (with severe hindlimb weakness) and atrophy and decreased TH-staining of dopaminergic neurons in the substantia nigra. Competition between β-sitosterol and cholesterol was implicated in the damage. It is not known whether Chamorros of Guam have genetic abnormalities affecting LXRβ.

    A related study was presented at the SfN meeting in San Diego. Paul Yarowsky of University of Maryland School of Medicine in Baltimore fed washed cycad seed flour to adult male Sprague-Dawley rats (McDowell et al., poster 686.3/I8, find abstract). After 12 weeks of feeding, a spontaneous rotating behavior was observed, and motor testing was consistent with parkinsonism. Histology revealed loss of tyrosine hydroxylase immunoreactive SNpc neurons.

    Neither of these animal studies has resulted in tau pathology in the mice or rats, but tau lesions have typically been difficult to produce in rodents without overexpressing or mutating the tau gene.

    For now, these findings are intriguing and provide circumstantial evidence in support of the cycad hypothesis. At the very least, these are interesting animal models in their own right, and they are likely to encourage further cross-talk between human and animal studies.

    References:

    Miller G. Neurodegenerative disease. Guam's deadly stalker: on the loose worldwide?. Science. 2006 Jul 28;313(5786):428-31. PubMed.

    Galasko D, Salmon D, Gamst A, Olichney J, Thal LJ, Silbert L, Kaye J, Brooks P, Adonay R, Craig UK, Schellenberg G, Borenstein AR. Prevalence of dementia in Chamorros on Guam: relationship to age, gender, education, and APOE. Neurology. 2007 May 22;68(21):1772-81. PubMed.

    Sundar PD, Yu CE, Sieh W, Steinbart E, Garruto RM, Oyanagi K, Craig UK, Bird TD, Wijsman EM, Galasko DR, Schellenberg GD. Two sites in the MAPT region confer genetic risk for Guam ALS/PDC and dementia. Hum Mol Genet. 2007 Feb 1;16(3):295-306. PubMed.

    Khabazian I, Bains JS, Williams DE, Cheung J, Wilson JM, Pasqualotto BA, Pelech SL, Andersen RJ, Wang YT, Liu L, Nagai A, Kim SU, Craig UK, Shaw CA. Isolation of various forms of sterol beta-D-glucoside from the seed of Cycas circinalis: neurotoxicity and implications for ALS-parkinsonism dementia complex. J Neurochem. 2002 Aug;82(3):516-28. PubMed.

    Wilson JM, Khabazian I, Wong MC, Seyedalikhani A, Bains JS, Pasqualotto BA, Williams DE, Andersen RJ, Simpson RJ, Smith R, Craig UK, Kurland LT, Shaw CA. Behavioral and neurological correlates of ALS-parkinsonism dementia complex in adult mice fed washed cycad flour. Neuromolecular Med. 2002;1(3):207-21. PubMed.

    View all comments by Douglas Galasko

  2. This study by Kim et al. extends the Gustafsson group’s previous work on the role of nuclear liver X receptor β (LXRβ) in neurodegeneration (1,2). This time the investigators have compared the effect of a diet rich in β-sitosterol in LXRβ knockout and wild-type mice. The results show that the administration of this plant sterol caused cell death of the large spinal motor neurons of lateroventral horns L1 segments in the LXRβ-/- but not the wild-type mice. Furthermore, there was a loss of tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra of LXRβ-/- mice, with no remarkable effects on neuronal morphology in the substantia nigra of WT mice.

    It should be mentioned that earlier work from this group demonstrated that LXRβ-/- mice develop motor neuron disease (ALS) as they age, and sitosterol exacerbated the phenotype (3). For example, similarly to ALS, ubiquitin and low-molecular-weight neurofilament mRNA-binding protein TDP-43 immunoreactivity is observed in the cytoplasm of large spinal cord motor neurons of both vehicle and sitosterol-treated LXRβ mice.

    β-sitosterol is abundant in plant oils and, similar to cholesterol and hydroxysterols, is a ligand for LXRα and LXRβ. Previous studies by another group demonstrated that male mice fed cycad flour rich in β-sitosterol-glucoside developed a phenotype reminiscent of ALS-parkinsonism dementia complex (ALS-PDC) (4,5). Most importantly, epidemiological studies show a positive correlation between consumption of cycad seed common in Guam and occurrence of ALS-PDC.

    The increased level of plasma sitosterol is observed in sitosterolemia—a rare recessive disorder caused by gene mutations in either ABCG5 or ABCG8. The sitosterolemia is characterized by impaired biliary and intestinal sterol secretion, sterol accumulation, and premature atherosclerosis, but not by neurodegeneration or dementia. Moreover, the plant sterols are dramatically increased in the brains of ABCG5 and ABCG8 knockout mice, but no neurodegenerative phenotype was reported (6).

    Some questions remain to be answered yet:

    • What is the molecular mechanism behind LXRβ and its role in this phenotype? Expression profiling in brains of treated mice is one way to address this question. Such an approach is being increasingly applied with other animal models of neurodegeneration (7), and Gustafsson’s group was one of the first to publish gene array results in LXRα and LXRβ knockout mice (2).
    • Is it only LXRβ, or could LXRα global deletion lead to a similar phenotype? The role of LXR in Alzheimer disease, for example, has been confirmed in a number of studies using a variety of approaches, and none of those has shown a definitive distinction between the two of the receptors (8).
    • Why is the phenotype gender-specific? Could it be related to LXR targets differentially expressed in a gender-specific manner?
    • And finally—who is the real culprit? Is it sitosterol or its metabolites, and if so, which metabolite?
    • The exact answers will likely strengthen the understanding that the LXR-mediated transcriptional regulation in CNS is important for normal neuronal function and plays a role in the pathogenesis of neurodegenerative disorders.

    References:

    Kim HJ, Fan X, Gabbi C, Yakimchuk K, Parini P, Warner M, Gustafsson JA. Liver X receptor beta (LXRbeta): a link between beta-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2094-9. PubMed.

    Wang L, Schuster GU, Hultenby K, Zhang Q, Andersson S, Gustafsson JA. Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13878-83. PubMed.

    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.

    Tabata RC, Wilson JM, Ly P, Zwiegers P, Kwok D, Van Kampen JM, Cashman N, Shaw CA. Chronic exposure to dietary sterol glucosides is neurotoxic to motor neurons and induces an ALS-PDC phenotype. Neuromolecular Med. 2008;10(1):24-39. PubMed.

    Wilson JM, Shaw CA. Late appearance of glutamate transporter defects in a murine model of ALS-parkinsonism dementia complex. Neurochem Int. 2007 Jun;50(7-8):1067-77. PubMed.

    Jansen PJ, Lütjohann D, Abildayeva K, Vanmierlo T, Plösch T, Plat J, von Bergmann K, Groen AK, Ramaekers FC, Kuipers F, Mulder M. Dietary plant sterols accumulate in the brain. Biochim Biophys Acta. 2006 Apr;1761(4):445-53. PubMed.

    Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R. Expression profiling in APP23 mouse brain: inhibition of Abeta amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener. 2007;2:20. PubMed.

    Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, Vinters HV, Tontonoz P. Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10601-6. PubMed.

    View all comments by Radosveta Koldamova

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