Figure 1.

The toxic metal hypothesis for neurological disorders. Human exposure to multiple toxic metals results in selective uptake of the metals into locus ceruleus neurons. Decreased noradrenaline from the locus ceruleus causes multifocal damage to the blood–brain barrier, allowing toxic metal uptake by astrocytes. A second pathway is slower age-related accumulation of toxic metals through an intact blood–brain barrier. Toxic metals in astrocytes cause astrocyte dysfunction, and transfer of metals from astrocytes triggers neuronal and oligodendrocyte malfunction. The degree of toxic metal-induced damage to these cells differs due to genetic variants and different combinations of toxic metals, leading to varying clinical outcomes. Uptake of toxic metals by extra-CNS organs is responsible for systemic disorders associated with neurological disorders. Uptake of toxic metals by striated muscles is followed by retrograde transport of metals to the lower motor neurons affected by ALS.