Etiology of Retinal and Cerebellar Pathology in Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex

Overview

Journal Eye Brain

Publisher Dove Medical Press

Date 2020 Aug 9

PMID 32765151

Citations 9

Authors

Peter S Spencer

Affiliations

Soon will be listed here.

Abstract

Purpose: To reexamine the etiology of a unique retinal pathology (linear and vermiform sub-retinal tubular structures) described among subjects with and without neurodegenerative disease in former high-incidence foci of Western Pacific amyotrophic lateral sclerosis and parkinsonism-dementia complex (ALS/PDC) in Guam (USA) and the Kii peninsula of Honshu island (Japan).

Methods: Analysis of published and unpublished reports of 1) ALS/PDC and the retinal and cerebellar pathology associated therewith and 2) exogenous neurotoxic factors associated with ALS/PDC and the developing retina and cerebellum.

Results: ALS/PDC retinal and cerebellar pathology matches persistent retinal and cerebellar dysplasia found in laboratory animals given single in utero or postnatal systemic treatment with cycasin, the principal neurotoxic component in the seed of cycad plants traditionally used for food (Guam) or oral medicine (Kii-Japan), both of which have been linked to the human neurodegenerative disease.

Conclusion: ALS/PDC-associated retinal and cerebellar dysplasia could arise from in utero exposure to methylazoxymethanol, the genotoxic metabolite of cycasin that results from maternal ingestion of this azoxyglucoside. These results support the environmental toxic etiology of retinal and brain pathology in ALS/PDC.

Citing Articles

Introducing the Role of Genotoxicity in Neurodegenerative Diseases and Neuropsychiatric Disorders.

Kisby G, Wilson 3rd D, Spencer P Int J Mol Sci. 2024; 25(13).

PMID: 39000326 PMC: 11241460. DOI: 10.3390/ijms25137221.

Concerns with the new biological research criteria for synucleinopathy.

Reis J, Tranchant C, Lucchini R, Spencer P Lancet Neurol. 2024; 23(7):663.

PMID: 38876740 PMC: 11344483. DOI: 10.1016/S1474-4422(24)00215-1.

Reply to: Questioning the cycad theory of Kii ALS-PDC causation.

Mensikova K, Rosales R, Colosimo C, Spencer P, Lannuzel A, Ugawa Y Nat Rev Neurol. 2024; 20(3):195-196.

PMID: 38336911 DOI: 10.1038/s41582-024-00938-y.

Endemic parkinsonism: clusters, biology and clinical features.

Mensikova K, Steele J, Rosales R, Colosimo C, Spencer P, Lannuzel A Nat Rev Neurol. 2023; 19(10):599-616.

PMID: 37684518 DOI: 10.1038/s41582-023-00866-3.

Early-onset, conjugal, twin-discordant, and clusters of sporadic ALS: Pathway to discovery of etiology lifetime exposome research.

Spencer P, Palmer V, Kisby G, Lagrange E, Horowitz B, Angues R Front Neurosci. 2023; 17:1005096.

PMID: 36860617 PMC: 9969898. DOI: 10.3389/fnins.2023.1005096.

References

Hira N, Marciniak M, PENNER S . Ophthalmomyiasis interna posterior and pigmentary retinopathy of Guam. J Am Optom Assoc. 1997; 68(7):452-8. View

Jones M, Yang M, MICKELSEN O . Effects of methylazoxymethanol glucoside and methylazoxymethanol acetate on the cerebellum of the postnatal Swiss albino mouse. Fed Proc. 1972; 31(5):1508-11. View

Matsumoto H, Spatz M, LAQUEUR G . Quantitative changes with age in the DNA content of methylazoxymethanol-induced microencephalic rat brain. J Neurochem. 1972; 19(2):297-306. DOI: 10.1111/j.1471-4159.1972.tb01339.x. View

Shimada M, LANGMAN J . Repair of the external granular layer of the hamster cerebellum after prenatal and postnatal administration of methylazoxymethanol. Teratology. 1970; 3(2):119-33. DOI: 10.1002/tera.1420030204. View

Spencer P, Palmer V, Kihira T, Yoshida S, Reis J, Yabushita M . Kampō medicine and Muro disease (Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex). eNeurologicalSci. 2020; 18:100230. PMC: 7026288. DOI: 10.1016/j.ensci.2020.100230. View

Kisby G, Olivas A, Park T, Churchwell M, Doerge D, Samson L . DNA repair modulates the vulnerability of the developing brain to alkylating agents. DNA Repair (Amst). 2009; 8(3):400-12. PMC: 2692311. DOI: 10.1016/j.dnarep.2008.12.002. View

Karlsson O, Berg C, Brittebo E, Lindquist N . Retention of the cyanobacterial neurotoxin beta-N-methylamino-l-alanine in melanin and neuromelanin-containing cells--a possible link between Parkinson-dementia complex and pigmentary retinopathy. Pigment Cell Melanoma Res. 2009; 22(1):120-30. DOI: 10.1111/j.1755-148X.2008.00508.x. View

Nagata Y, Matsumoto H . Studies on methylazoxymethanol: methylation of nucleic acids in the fetal rat brain. Proc Soc Exp Biol Med. 1969; 132(1):383-5. DOI: 10.3181/00379727-132-34220. View

Kokubo Y, Ito K, Kuzuhara S . Ophthalmomyiasis-like pigmentary retinopathy in ALS/PDC in the Kii peninsula of Japan. Neurology. 2003; 60(10):1725-6. DOI: 10.1212/01.wnl.0000061487.16841.72. View

10.

Hartkop T, Jones M . Methylazoxymethanol-induced aberrant Purkinje cell dendritic development. J Neuropathol Exp Neurol. 1977; 36(3):519-32. DOI: 10.1097/00005072-197705000-00009. View

11.

Lai H, Quock R, Makous W, Horita A, Jen L . Methylazoxymethanol acetate: effect of postnatal injection on brain amines and behavior. Pharmacol Biochem Behav. 1978; 8(3):251-7. DOI: 10.1016/0091-3057(78)90312-x. View

12.

Srivenugopal K, Yuan X, Friedman H, Ali-Osman F . Ubiquitination-dependent proteolysis of O6-methylguanine-DNA methyltransferase in human and murine tumor cells following inactivation with O6-benzylguanine or 1,3-bis(2-chloroethyl)-1-nitrosourea. Biochemistry. 1996; 35(4):1328-34. DOI: 10.1021/bi9518205. View

13.

Steele J, Wresch R, Hanlon S, Keystone J, Ben-Shlomo Y . A unique retinal epitheliopathy is associated with amyotrophic lateral sclerosis/Parkinsonism-Dementia complex of Guam. Mov Disord. 2015; 30(9):1271-5. DOI: 10.1002/mds.26264. View

14.

Spatz M, Dougherty W, Smith D . Teratogenic effects of methylazoxymethanol. Proc Soc Exp Biol Med. 1967; 124(2):476-8. DOI: 10.3181/00379727-124-31767. View

15.

SLUSHER M, HOLLAND W, Weaver R, Tyler M . Ophthalmomyiasis interna posterior. Subretinal tracks and intraocular larvae. Arch Ophthalmol. 1979; 97(5):885-7. DOI: 10.1001/archopht.1979.01020010443008. View

16.

Kurland L . PROCEEDINGS OF THE THIRD CONFERENCE ON THE TOXICITY OF CYCADS. INTRODUCTORY REMARKS. Fed Proc. 1964; 23:1337-9. View

17.

Latker C, Eiden L, Zatz M . The effect of methylazoxymethanol acetate (MAM) on the developing rat retina. Exp Eye Res. 1982; 35(4):351-61. DOI: 10.1016/0014-4835(82)90098-7. View

18.

Tao Z, Wang Y, Yu S, Yin Z, Liu Y, Li S . Hookworm in the eye. Lancet Infect Dis. 2018; 18(5):582. DOI: 10.1016/S1473-3099(18)30097-5. View

19.

Hanlon S, Steele J . An unusual retinal pigment epitheliopathy endemic to the island of Guam. Optom Vis Sci. 1993; 70(10):854-9. DOI: 10.1097/00006324-199310000-00014. View

20.

Johnston M, Grzanna R, Coyle J . Methylazoxymethanol treatment of fetal rats results in abnormally dense noradrenergic innervation of neocortex. Science. 1979; 203(4378):369-71. DOI: 10.1126/science.32620. View