Therapeutic Strategies and Metal-Induced Oxidative Stress: Application of Synchrotron Radiation Microbeam to Amyotrophic Lateral Sclerosis in the Kii Peninsula of Japan

Abstract

A series of extensive gene-environment studies on amyotrophic lateral sclerosis (ALS) and Parkinsonism–dementia complex (PDC) in Guam Island, USA, and the Kii Peninsula of Japan, including Auyu Jakai, West New Guinea, have led us to hypothesize that a prolonged low calcium (Ca) and magnesium (Mg) intake, especially over generation, may cause oxidative stress to motor and nigral neurons by an increased uptake of environment metallic elements, i.e., aluminum (Al), manganese (Mn), and iron (Fe). Otherwise, 5–10% of total ALS cases are familial ALS (fALS), of which 20% of the fALS cases linked to a point mutation of Cu/Zn superoxide dismutase (SOD1). In the vicinity of the Kii Peninsula, about 7% of the ALS cases are also linked to the SOD1 mutation. Using synchrotron radiation (SR) microbeam, conglomerate inclusion (SOD1 aggregates) within a spinal motor neuron of the fALS case in the vicinity revealed a loss of copper (Cu) in contrast to extremely high contents of Zinc (Zn) and Ca. That means an exceptionally low Cu/Zn ratio with an increased Ca content, indicating the abnormalities of the active site of SOD1 protein of the fALS. Furthermore, sALS in the southernmost high incidence areas of the Kii Peninsula showed a low Cu/Zn ratio within a motor neuron, suggesting a fragility of SOD1 proteins. From the perspective of gene–environment interactions, the above two research trends may show a common oxidative stress underlying the neuronal degenerative process of ALS/PDC in the Kii Peninsula of Japan. Therefore, it is a crucial point for the prospect of therapeutic strategy to clarify a role of transition metals in the oxidative process in both ALS/PDC, including ALS elsewhere in the world. This paper reviews a history of the genetic epidemiological studies, especially from the aspect of gene–environment interaction, on ALS/PDC in the Kii and Guam high incidence foci and the results of a series of analytical research on trace metallic elements within neurons of both sALS and fALS cases, especially using a synchrotron radiation (SR) microbeam of Spring-8 and Photon Factory of Japan. The SR microbeam is an ideal X-ray source, which supplies an extremely high brilliance (high-intensity photon) and tunability (energy variability) to investigate trace metallic elements contained in biological specimens at the cellular level, even more without any damages. This research will provide a valuable information about the mechanism of oxidative stress involved in neuronal cell death in ALS and related neurodegenerative disorders. To elucidate the physicochemical mechanism of the oxidative process in neuronal degeneration, it will shed a new light on the therapeutic strategies for ALS/PDC in near future.

Raw Water and ALS: A Unifying Hypothesis for the Environmental Agents Involved in ALS

“… 105 In Guam, the Chamorros used rainwater from tin roofs and ground surface water as drinking water, containing extremely low contents of Ca and Mg, and in Oshima, a small island opposite to the top of the mainland of the Kii Peninsula, the water source was changed from the Kozagawa river, in which the Ca and Mg contents were extremely low. 88 , 104 …”

“…105 In Guam, the Chamorros used rainwater from tin roofs and ground surface water as drinking water, containing extremely low contents of Ca and Mg, and in Oshima, a small island opposite to the top of the mainland of the Kii Peninsula, the water source was changed from the Kozagawa river, in which the Ca and Mg contents were extremely low. 88,104 At last, it is important to underline the recent evidence on the effectiveness of the UV/chlorine process for the treatment of BMAA-contained water. 105 Overall, the use of raw water could be the vehicle by which the human organism is exposed to toxins, metals, microorganisms, or deficient concentrations of minerals that may be involved in the etiopathogenetic mechanism of ALS by interacting with genetic susceptibility factors.…”

Distribution of Iron, Copper, Zinc and Cadmium in Glia, Their Influence on Glial Cells and Relationship with Neurodegenerative Diseases

“…The possible connection between trace elements abnormalities and ALS is under consideration. For example, some research showed increased iron accumulation in the neurons of the ALS-affected patients, especially in microglia, which, due to the Fenton reaction, may induce an oxidative stress in the cells, causing damage to these neurons [ 17 , 27 , 28 , 209 ]. Oxidative stress can also be induced by high cadmium [ 29 ] and copper levels [ 12 , 17 ], or by low and high zinc levels [ 12 , 17 ].…”

“…For example, edaravone treatment aims to reduce the oxidative stress in the neurons, as well as regulating-activated microglia [ 211 ]. There have been attempts to use chelators as a therapy, but this kind of treatment still needs more research to show its usefulness in ALS patients [ 209 ]. Deferiprone is an iron chelator, which is currently being tested as a possible neuroprotective drug in ALS [ 210 , 212 ].…”