Age-Related Uptake of Heavy Metals in Human Spinal Interneurons

Abstract

Toxic heavy metals have been implicated in the loss of spinal motoneurons in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Motoneuron loss in the spinal anterior horn is severe in ALS/MND at the time of death, making this tissue unsuitable for examination. We therefore examined spinal cords of people without muscle weakness to look for any presence of heavy metals that could make these neurons susceptible to damage. Spinal cord samples from 50 individuals aged 1–95 y who had no clinical or histopathological evidence of spinal motoneuron loss were studied. Seven μm formalin-fixed paraffin-embedded sections were stained for heavy metals with silver nitrate autometallography (AMGHM) which detects intracellular mercury, silver or bismuth. Neurons in the spinal cord were classified as interneurons or α-motoneurons based on their site and cell body diameter. Spinal interneurons containing heavy metals were present in 8 of 24 people (33%) aged 61–95 y, but not at younger ages. These AMGHM interneurons were most numerous in the lumbar spinal cord, with moderate numbers in the caudal cervical cord, few in the rostral cervical cord, and almost none in the thoracic cord. All people with AMGHM interneurons had occasional AMGHM staining in α-motoneurons as well. In one man AMGHM staining was present in addition in dorsomedial nucleus and sensory neurons. In conclusion, heavy metals are present in many spinal interneurons, and in a few α-motoneurons, in a large proportion of older people. Damage to inhibitory interneurons from toxic metals in later life could result in excitotoxic injury to motoneurons and may underlie motoneuron injury or loss in conditions such as ALS/MND, multiple sclerosis, sarcopenia and calf fasciculations.

Healing of Amyotrophic Lateral Sclerosis: A Case Report

“…Mercury accumulates in interneurons and to a lesser degree in α-motoneurons, in amounts increasing with age. This may lead to motor neuron death and thus provides support to the view that exposure to mercury may be a contributing factor to ALS in susceptible individuals [19].…”

Inorganic mercury in human astrocytes, oligodendrocytes, corticomotoneurons and the locus ceruleus: implications for multiple sclerosis, neurodegenerative disorders and gliomas

“…ALS is suspected to originate in corticomotoneurons (Eisen and Weber 2001 ) so it is of interest that mercury inhibits astrocytic glutamate uptake, leaving more of this excitatory amino acid in the synaptic cleft to damage the neuron (Shanker et al 2003 ). The finding of iHg in corticomotoneurons and in other neurons implicated in ALS (Pamphlett and Kum Jew 2016 ) raises the possibility that iHg exerts its neurotoxic effect by binding to cysteine that forms the intra-superoxide dismutase 1 disulphide bonds, thereby preventing its normal folding and leading to misfolded forms of the protein (Sea et al 2015 ); this has been found in the spinal cord in both familial and sporadic ALS (Gruzman et al 2007 ) and by this mechanism iHg could produce a neurotoxic phenocopy of superoxide dismutase 1-mutant ALS. Numerous other functions of astrocytes have been suggested to be disturbed in ALS (Yamanaka and Komine 2018 ) and motor neuron death can be triggered by astrocytes (Re et al 2014 ).…”

Epigenetic differences between monozygotic twins discordant for amyotrophic lateral sclerosis (ALS) provide clues to disease pathogenesis

“…Of note, the only therapeutic agent to slow the progress of ALS, riluzole, has a predominantly anti-glutamate action. A recent report of mercury uptake into human GABA-producing spinal interneurons [ 52 ], with the possibility that these damaged interneurons predispose the motor neurons to excitotoxic damage [ 53 ], emphases the importance of these pathways in ALS. Our findings of epigenetic differences in these pathways add further evidence to the proposal that excitotoxic motor neuron damage, which could be therapeutically modified, is an important mechanism in ALS.…”