The Why of Sporadic Motor Neuron Disease - Many Factors, still a Mystery?

Abstract

The sporadic forms of motor neuron diseases seem to depend on a multitude of factors that are, however, largely speculative. A main endogenous factor is seen in the enhanced expression of human endogenous retroviruses (HERVs). It is supposed that this is affecting the biogenesis of neuromelanin, in particular in the locus coeruleus. An altered neuromelanin with increased storage of metals and of precursors for toxins from food, respectively, might be of central importance. A hypothesis is described that is able to explain a number of observations and to understand roles and interactions of different factors. Toxins affecting the excitatory system are formed apparently within altered neuromelanin. Moreover, neuromelanin loaded with metal is also a microenvironment where pathological variants of proteins such as of alphasynuclein are generated. Familial and toxin related forms of the diseases merge in formation and deposition of aberrant proteins and in a failure to destroy superoxide, thus increasing the harm from oxidative and nitrosative stress. This view might give some rational to revive investigations in methods for stabilization of storage and cautious squeezing out of metals and toxicants from neuromelanin, relying eventually on melatonin, iron chelators and chloroquine, respectively.

Cellular and Molecular Aspects of the β-N-Methylamino-l-alanine (BMAA) Mode of Action within the Neurodegenerative Pathway: Facts and Controversy

“…The auto-oxidation process of catecholamines is supposed to be a major source of neuromelanin [ 72 ]. The substrate involved in this oxidative polymerization is either norepinephrine in the locus coeruleus or dopamine in the SN and most other brain areas [ 73 , 74 ], this latter being an essential neurotransmitter for the striatal control [ 75 ]. The synthesis of neuromelanin could then prevent the accumulation of dopamine-oxidation products such as cyclized quinones (DA o -quinone, aminochrome and 5,6-indolequinone).…”