Neurotoxicity Research

, Volume 33, Issue 1, pp 192–198 | Cite as

Studies of Environmental Risk Factors in Amyotrophic Lateral Sclerosis (ALS) and a Phase I Clinical Trial of l-Serine

  • Walter G. Bradley
  • R. X. Miller
  • T. D. Levine
  • E. W. Stommel
  • P. A. Cox
ORIGINAL ARTICLE

Abstract

β-N-Methylamino-l-alanine (BMAA) has been linked to Guam ALS/PDC and shown to produce neurodegeneration in vitro and in vivo (Drosophila, mice, rats, primates). BMAA misincorporation into neuroproteins produces protein misfolding and is inhibited by l-serine. Case-control studies in Northern New England indicate that living near to water-bodies with cyanobacterial blooms increases the risk of developing amyotrophic lateral sclerosis (ALS). The distribution of addresses of ALS cases in New Hampshire, Vermont, and Florida was compared to that of controls. Areas of statistically significantly increased numbers of ALS cases were examined for sources of environmental toxins. A phase I trial of oral l-serine was performed in 20 ALS patients (0.5 to 15 g twice daily). Safety and tolerability were assessed by comparing the rate of deterioration with 430 matched placebo controls. The distribution of residential addresses of ALS cases in New England and Florida revealed many areas where the age- and gender-adjusted frequency of ALS was greater than expected (P < 0.01). GIS studies of these “hot spots” in relation to sources of environmental pollutants, like cyanobacterial blooms, Superfund and Brownfield sites, and landfills, are ongoing. In the phase I trial of l-serine, two patients withdrew from because of gastrointestinal side effects. Three patients died during the study, which was about the expected number. The ALSFRS-R in the l-serine-treated patients showed a dose-related decrease in the rate of progression (34% reduction in slope, P = 0.044). The non-random distribution of addresses of ALS patients suggests that residential exposure to environmental pollutants may play an important role in the etiology of ALS. l-Serine in doses up to 15 g twice daily appears to be safe in patients with ALS. Exploratory studies of efficacy suggested that l-serine might slow disease progression. A phase II trial is planned.

Keywords

Amyotrophic lateral sclerosis Treatment l-Serine Environmental epidemiology Cyanobacteria BMAA 

References

  1. Abhinav K, Al-Chalabi A, Hortobagyi T, Leigh PN (2007) Electrical injury and amyotrophic lateral sclerosis: a systematic review of the literature. J Neurol Neurosurg Psychiatry 78:450–453CrossRefPubMedGoogle Scholar
  2. Al-Chalabi A, Calvo A, Chio A, Colville S et al (2014) Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study. Lancet Neurol 13:1108–1113CrossRefPubMedPubMedCentralGoogle Scholar
  3. ALSUntangled Group (2017) ALSUntangled 38: L-serine. Amyotrophic lateral sclerosis and Frontotemporal Degeneration 18:148–151CrossRefGoogle Scholar
  4. Andrew AS, Caller TA, Tandan R, Duell EJ et al (2017) Environmental and occupational exposures and ALS in New England. Neurodegener Dis 17:110–116CrossRefPubMedGoogle Scholar
  5. Banack SA, Cox PA (2002) Biomagnification of cycad neurotoxins in flying foxes: implications for ALS-PDC in Guam. Neurology 61(3):387–389CrossRefGoogle Scholar
  6. Banack SA, Murch SJ, Cox PA (2006) Neurotoxic flying foxes as dietary items for the Chamorro people, Marianas Islands. J Ethnopharmacol 106(1):97–104CrossRefPubMedGoogle Scholar
  7. Banack SA, Caller TA, Stommel EW (2010a) The cyanobacteria derived toxin beta-N-methylamino-L-alanine and amyotrophic lateral sclerosis. Toxins (Basel) 2:2837–2850CrossRefPubMedCentralGoogle Scholar
  8. Banack SA, Cox PA, Murch SJ (2010b) Flying fox consumption and human neurodegenerative disease in Guam. In: Fleming TH, Racey PA (eds) Island bats: evolution, ecology, and conservation. University of Chicago Press, Chicago 2010: 341-366 Google Scholar
  9. Beard JD, Kamel F (2015) Military service, deployments, and exposures in relation to amyotrophic lateral sclerosis etiology and survival. Epidemiol Rev 37:55–70CrossRefPubMedGoogle Scholar
  10. Belbasis L, Bellou V, Evangelou E (2016) Environmental risk factors and amyotrophic lateral sclerosis: an umbrella review and critical assessment of current evidence from systematic reviews and meta-analyses of observational studies. Neuroepidemiology 46:96–105CrossRefPubMedGoogle Scholar
  11. Bell EA (2009) The discovery of BMAA, and examples of biomagnification and protein incorporation involving other non-protein amino acids. Amyotroph Lateral Scler 10(Supplement 2):21–25CrossRefPubMedGoogle Scholar
  12. Berntzon L, Ronnevi LO, Bergman B, Eriksson J (2015) Detection of BMAA in the human central nervous system. Neuroscience 292:137–147CrossRefPubMedGoogle Scholar
  13. Bonvicini F, Marcello N, Mandrioli J, Pietrini V, Vinceti M (2010) Exposure to pesticides and risk of amyotrophic lateral sclerosis: a population-based case-control study. Ann Ist Super Sanita 46:284–287PubMedGoogle Scholar
  14. Boyer GL, Watzin MC, Shambaugh AD, Satchwell MF, Rosen BH, Mihuc T (2004) The occurrence of cyanobacteria toxins in Lake Champlain. In: Manley TO, Manley PL, Mihuc TB (eds) Lake Champlain: partnerships and research in the new millennium. Kluwer Academic/Plenum Press, New York, pp 241–258CrossRefGoogle Scholar
  15. Bradley WG, Mash DC (2009) Beyond Guam: the cyanobacteria BMAA hypothesis of the cause of ALS and other neurodegenerative diseases. Amyotroph Lateral Scler 10(Supplement 2):7–20CrossRefPubMedGoogle Scholar
  16. Brand LE, Pablo J, Compton A, Hammerschlag N, Mash DC (2010) Cyanobacterial blooms and the occurrence of the neurotoxin beta-N-methylamino-L-alanine (BMAA) in South Florida aquatic food webs. Harmful Algae 9(6):620–635CrossRefPubMedPubMedCentralGoogle Scholar
  17. Burns CJ, Beard KK, Cartmill JB (2001) Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945-94: an update. Occup Environ Med 58:24–30CrossRefPubMedPubMedCentralGoogle Scholar
  18. Caller TA, Doolin JW, Haney JF, Murby AJ, West KG, Farrar HE et al (2009) A cluster of amyotrophic lateral sclerosis in New Hampshire: a possible role for toxic cyanobacteria blooms. Amyotroph Lateral Scler 10(Suppl. 2):101–108CrossRefPubMedGoogle Scholar
  19. Caller TA, Field NC, Chipman JW, Shi X, Harris BT, Stommel EW (2012) Spatial clustering of amyotrophic lateral sclerosis and the potential role of BMAA. Amyotroph Lateral Scler 13(1):25–32CrossRefPubMedGoogle Scholar
  20. Codd GA (2000) Cyanobacterial toxins, the perception of water quality and the prioritization of eutrophication control. Ecol Eng 16:51–60CrossRefGoogle Scholar
  21. Codd GA, Lindsay J, Young FM, Morrison LF, Metcalf J (2005a) Harmful cyanobacteria: from mass mortalities to management measures. In: Huisman J, Matthijs HCP, Visser PM (eds) Harmful cyanobacteria. Springer, Dordrecht, pp 1–23Google Scholar
  22. Codd GA, Azevedo SMFO, Bagchi SN, Burch MD, Carmichael WW, Harding WR, et al. (2005b) CYANONET: a global network for cyanobacterial bloom and toxin risk management. http://www.unesco.org
  23. Codd GA, Morrison LF, Metcalf JS (2005c) Cyanobacterial toxins: risk management for health protection. Toxicol Appl Pharmacol 203:264–272CrossRefPubMedGoogle Scholar
  24. Corcia P, Jafari-Schluep HF, Lardillier D, Mazyad H, Giraud P, Clavelou P, Pouget J, Camu W (2003) A clustering of conjugal ALS in southeastern France. Arch Neurol 60:553–557CrossRefPubMedGoogle Scholar
  25. Costa J, Swash M, de Carvalho M (2012) Awaji criteria for the diagnosis of ALS. Arch Neurol 69:1410–1416CrossRefPubMedGoogle Scholar
  26. Cox PA, Sacks OW (2002) Cycad neurotoxin, consumption of fruit bats, and ALS/PDC disease in Guam. Neurology 59(10):1664–1665CrossRefGoogle Scholar
  27. Cox PA, Banack SA, Murch SJ (2003) Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Nat Acad Sci 100(23):13380–13383CrossRefPubMedPubMedCentralGoogle Scholar
  28. Cox PA, Banack SA, Murch SJ (2007) Cyanobacteria, cycads, and neurodegenerative disease among the Chamorro People of Guam. In: Vovides, Andrew P., Stevenson, Dennis 5 Wm., Osborne, Roy, editors. Proceedings of Cycad 2005: The 7th International Conference on Cycad Biology. New York: New York Botanical Garden Press, :253–285Google Scholar
  29. Cox PA, Davis DA, Mash DC, Metcalf JS, Banack SA (2016) Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain. Proc R Soc B 283:20152397CrossRefPubMedPubMedCentralGoogle Scholar
  30. De Koning TJ (2006) Treatment with amino acids in serine deficiency disorders. J Inherit Metab Dis 29:347–351CrossRefPubMedGoogle Scholar
  31. Dunlop R, Rodgers K (2011) Proteins containing BMAA form autofluorescent aggregates and induce cell death. Amyotroph Lateral Scler 12(Suppl 1):156Google Scholar
  32. Dunlop RA, Cox PA, Banack SA, Rodgers KJ (2013) The non-protein amino acid BMAA is misincorporated into human proteins in place of L-serine causing protein misfolding and aggregation. PLoS One 8(9)Google Scholar
  33. Dunlop RA, Powell J, Heng B, Guillemin GJ, Cox PA (2017) L-Serine induces neuroprotection in the brain by alerting CHOP without activating the unfolded protein response. PLOS-One, submittedGoogle Scholar
  34. Fang F, Quinlan P, Ye W, Barber MK, Umbach DM, Sandler DP, Kamel F (2009) Workplace exposures and the risk of amyotrophic lateral sclerosis. Environ Health Perspect 117:1387–1392CrossRefPubMedPubMedCentralGoogle Scholar
  35. Fogg GE, Stewart WDP, Fay P, Walsby AE (1973) The blue-green algae. Academic Press, London and NewYorkGoogle Scholar
  36. Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A et al (2011) Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest 121:4735–4745CrossRefPubMedPubMedCentralGoogle Scholar
  37. Gunnarsson LG, Lindberg G, Soderfeldt B, Axelson O (1991) Amyotrophic lateral sclerosis in Sweden in relation to occupation. Acta Neurol Scand 83:394–398CrossRefPubMedGoogle Scholar
  38. Institute of Medicine (US) (2005) Panel on Micronutrients. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein and amino acids. Panel on Macronutrients Panel on the Definition of Dietary Fiber, Subcommittee on Upper Reference Levels of Nutrients, Subcommittee on Interpretation and Uses of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board. National Academies PressGoogle Scholar
  39. Johnson FO, Atchison WD (2009) The role of environmental mercury, lead and pesticide exposure in development of amyotrophic lateral sclerosis. Neurotoxicology 30:761–765CrossRefPubMedPubMedCentralGoogle Scholar
  40. Jonasson S, Eriksson J, Berntzon L, Spácil Z, Ilag LL, Ronnevi LO et al (2010) Transfer of a cyanobacterial neurotoxin within a temperate aquatic ecosystem suggests pathways for human exposure. Proc Nat Acad Sci 107(20):9252–9257CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kurland LT, Mulder DW (1954) Epidemiologic investigations of amyotrophic lateral sclerosis: I. Preliminary report on geographic distribution, with particular reference to the Mariana Islands, including clinical and pathologic observations. Neurology 4:355–378 338-348 CrossRefPubMedGoogle Scholar
  42. Lee JW, Beebe K, Nangle LA, Jang J et al (2006) Editing-defective tRNA synthetase causes protein misfolding and neurodegeneration. Nature 443:50–55CrossRefPubMedGoogle Scholar
  43. Levine TD, Miller RG, Bradley WG, Moore DH et al (2016) Phase I clinical trial of safety of L-serine for ALS. Amyotroph Lateral Sclerosis and Frontotemporal Degen 2:1–5Google Scholar
  44. Malek AM, Barchowsky A, Bowser R et al (2014) Environmental and occupational risk factors for amyotrophic lateral sclerosis: a case-control study. Neurodegener Dis 14:31–38CrossRefPubMedGoogle Scholar
  45. Malek AM, Barchowsky A, Bowser R et al (2015) Exposure to hazardous air pollutants and the risk of amyotrophic lateral sclerosis. Environ Pollut 197:181–186CrossRefPubMedGoogle Scholar
  46. Massetet E, Banack S, Boumediene F, Abadie E et al (2013) Dietary BMAA exposure in an ALS cluster from southern France. PLoS One 8(12):e83406CrossRefGoogle Scholar
  47. McGuire V, Longstreth WT Jr, Nelson LM et al (1997) Occupational exposures and amyotrophic lateral sclerosis. A population-based case-control study. Am J Epidemiol 145:1076–1088CrossRefPubMedGoogle Scholar
  48. Mondo K, Hammerschlag N, Basile M, Pablo J et al (2012) Cyanobacterial neurotoxin β-N-methylamino-L-alanine (BMAA) in shark fins. Marine Drugs 10(2):509–520CrossRefPubMedPubMedCentralGoogle Scholar
  49. Murch SJ, Cox PA, Banack SA, Steele JC, Sacks OW (2004a) Occurrence of beta-methylamino-L-alanine (BMAA) in ALS/PDC patients from Guam. Acta Neurol Scand 110(4):267–269CrossRefPubMedGoogle Scholar
  50. Murch SJ, Cox PA, Banack SA (2004b) A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci 101:12228–12231CrossRefPubMedPubMedCentralGoogle Scholar
  51. Pablo J, Banack SA, Cox PA, Johnson TE, Papapetropoulos S et al (2009) Cyanobacterial neurotoxin BMAA in ALS and Alzheimer’s disease. Acta Neurol Scand 120(4):216–225CrossRefPubMedGoogle Scholar
  52. Paerl HW, Huisman J (2008) Blooms like it hot. Science 320:57–58CrossRefPubMedGoogle Scholar
  53. Paul VJ (2008) Global warming and cyanobacterial harmful algal blooms. Adv Exp Med Biol 619:239–257CrossRefPubMedGoogle Scholar
  54. Pupillo E, Messina P, Logroscino G, Zoccolella S et al (2012) Trauma and amyotrophic lateral sclerosis: a case-control study from a population-based registry. Eur J Neurol 19:1509–1517CrossRefPubMedGoogle Scholar
  55. Rodgers K, Dunlop R (2011) The cyanobacteria-derived BMAA can be incorporated into cell proteins and could thus be an environmental trigger for ALS and other neurological diseases associated with protein misfolding. Amyotroph Lateral Scler 12(Suppl 1):22Google Scholar
  56. Sabatelli M, Marangi G, Conte A et al (2016) New ALS-related genes expand the spectrum paradigm of ALS. Brain Pathol 26:266–275CrossRefPubMedGoogle Scholar
  57. Sabel CE, Gatrell AC, Löytönen M, Maasilta P, Jokelainen M (2000) Modeling exposure opportunities: estimating relative risk for motor neurone disease in Finland. Soc Sci Med 50:1121–1137CrossRefPubMedGoogle Scholar
  58. Sabel CE, Boyle PJ, Löytönen M, Gatrell AC, Jokelainen M, Flowerdew R, Maasilta P (2003) Spatial clustering of ALS in Finland at place of birth and place of death. Am J Epidemiol 157(10):898–905CrossRefPubMedGoogle Scholar
  59. Sabel CE, Boyle P, Raab G, Loytonen M, Maasilta P (2009) Modelling individual space-time exposure opportunities: a novel approach to unraveling the genetic or environmental disease causation debate. Spat Spatiotemporal Epidemiol 1:85–94CrossRefPubMedGoogle Scholar
  60. Schmidt S, Kwee LC, Allen KD, Oddone EZ (2010) Association of ALS with head injury, cigarette smoking and APOE genotypes. J Neurol Sci 291:22–29CrossRefPubMedPubMedCentralGoogle Scholar
  61. Shi X, Alford-Teaster J, Onega T (2009) Kernel density estimation with geographically masked points, in Proceedings of the 17th International Conference on Geoinformatics, Fairfax, VA, August 12–14. doi:  10.1109/GEOINFORMATICS.2009.5292881
  62. Sienko DG, Davis JP, Taylor JA, Brooks BR (1990) Amyotrophic lateral sclerosis. A case-control study following detection of a cluster in a small Wisconsin community. Arch Neurol 47(1):38–41CrossRefPubMedGoogle Scholar
  63. Stewart I, Webb PM, Schluter PJ, Shaw GR (2006) Recreational and occupational field exposure to freshwater cyanobacteria—a review of anecdotal and case reports, epidemiological studies and the challenges for epidemiologic assessment. Environ Health 5:6CrossRefPubMedPubMedCentralGoogle Scholar
  64. Stommel EW, Field NC, Caller TA (2013) Aerosolization of cyanobacteria as a risk factor for amyotrophic lateral sclerosis. Med Hypotheses 80:142–145CrossRefPubMedGoogle Scholar
  65. Su FC, Goutman SA, Chernyak S, Mukherjee B, Callaghan BC, Batterman S, Feldman EL (2016) Association of environmental toxins with amyotrophic lateral sclerosis. JAMA Neurol 73(7):803–811CrossRefPubMedPubMedCentralGoogle Scholar
  66. Sutedja NA, Fischer K, Veldink JH et al. (2008) What we truly know about occupation as a risk factor for ALS: a critical and systematic review. Amyotroph Lateral Scler 1–19Google Scholar
  67. Svircev Z, Krstic S, Miladinov-Mikov M, Baltic V, Vidovic M (2009) Freshwater cyanobacterial blooms and primary liver cancer epidemiological studies in Serbia. J Environ Sci Health C, Environ Carcinog Ecotoxicol Rev 27(1):36–55CrossRefGoogle Scholar
  68. Tabatabaie L, Klomp LW, Berger R, de Koning TJ (2010) L-Serine synthesis in the central nervous system: a review on serine deficiency disorders. Mol Genet Metab 99:256–262CrossRefPubMedGoogle Scholar
  69. Therrien M, Dion PA, Rouleau GA (2016) ALS: recent developments from genetic studies. Curr Neurol Neurosci Rep 16:59CrossRefPubMedGoogle Scholar
  70. Torbick N, Hession S, Stommel E, Caller T (2014) Mapping ALS lake risk factors across northern New England. Int J Health Geogr 13:1CrossRefPubMedPubMedCentralGoogle Scholar
  71. Weisskopf MG, McCullough ML, Morozova N, Calle EE et al (2005) Prospective study of occupation and amyotrophic lateral sclerosis mortality. Am J Epidemiol 162:1146–1152CrossRefPubMedGoogle Scholar
  72. Weisskopf MG, Cudkowicz ME, Johnson N (2015) Military service and amyotrophic lateral sclerosis in a population-based cohort. Epidemiology 26:831–838CrossRefPubMedPubMedCentralGoogle Scholar
  73. White MA, Sreedharan J (2016) ALS: recent genetic highlights. Curr Opin Neurol 29:557–564CrossRefPubMedGoogle Scholar
  74. Xie X, Basile M, Mash DC (2013) Cerebral uptake and protein incorporation of cyanobacterial toxin beta-N-methylamino-L-alanine. Neuroreport 24(14):779–784CrossRefPubMedGoogle Scholar
  75. Zhang F, Lee J, Liang S, Shum CK (2015) Cyanobacteria blooms and non-alcoholic liver disease. Environ Health 14:41CrossRefPubMedPubMedCentralGoogle Scholar
  76. Zufiria M, Gil-Bea FJ, Fernandez-Torron R et al (2016) ALS: a bucket of genes, environment, metabolism and unknown ingredients. Prog Neurobiol 142:104–129CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Walter G. Bradley
    • 1
  • R. X. Miller
    • 2
  • T. D. Levine
    • 3
  • E. W. Stommel
    • 4
  • P. A. Cox
    • 5
  1. 1.Department of Neurology, Miller School of MedicineUniversity of MiamiMiamiUSA
  2. 2.Forbes Norris MDA/ALS Research and Treatment CenterCalifornia Pacific Medical CenterSan FranciscoUSA
  3. 3.Phoenix Neurological AssociatesPhoenixUSA
  4. 4.Department of NeurologyGeisel School of Medicine at DartmouthHanoverUSA
  5. 5.Brain Chemistry LabsInstitute for EthnomedicineJacksonUSA

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