Tracemetals, neuromelanin and neurodegeneration: An interesting area for research

Abstract

Byline: T. Sathyanarayana Rao, Luigi. Zecca, K. Rao International Scenario The understanding of cellular neurodegeneration in brain disease is today's major challenge. The mapping of region-specific changes in the brain during neurodegeneration is a thrust area in neuroscience. Bipolar disorders are classical neuropsychiatric disorders where crosstalk between environmental factors and genetics plays an important role in the etiology of these disorders. Locus coeruleus (LC) is the main brain region containing norepinephrine neurons. The rostral projections from these neurons seem to be involved in the modulation of neuronal activity, metabolism and memory[sup] [1],[2] whereas the spinal cord projections are known to modulate spinal motoneuron function.[sup] [3],[4] Neuronal loss in LC occurs in Parkinson's disease (PD) and Alzheimer's disease and Down's syndrome[sup] [5],[6] in the midbrain regions. In Alzheimer's disease and Down's syndrome, it is not clear whether neuronal loss in LC is a primary event or a consequence of retrograde degeneration of cortically projecting cells due to the loss of cortical synapses. In PD, results have showed neuronal loss in substania nigra (SN) compared to LC.[sup] [5],[6],[7],[8] However, a recent study reported extensive impairment of LC neurons in PD.[sup] [9] SN and LC share anatomical and biochemical similarities, both being pigmented because of neuromelanin (NM) and both composed of catecholaminergic neurons. The relationship of factors like iron, ferritins and NM[sup] [10],[11],[12],[13],[14] to aging has been analyzed in previous studies. These factors may influence neuronal viability and undergo dramatic changes in PD. As aging is an important risk factor for PD, it would be relevant to establish the age-related changes in elements involved in oxidative stress like iron, copper and related molecules, all of which have been implicated as putative pathogenic factors. Due to their role in peroxidation, changes in iron, copper, their major storage proteins ferritin and ceruloplasmin (CP), together with the enzymes manganese-superoxide dismutase (SOD) and copper/zinc-SOD were determined in human SN and LC at various ages. Being a strong chelator of iron and other toxic metals,[sup] [14] NM has been shown to be a strong modulator of their cellular effects.[sup] [15],[16],[17] Luigi from the Italian group did a comparative analysis of metal-related neuronal vulnerability in two brainstem nuclei, the locus coeruleus (LC) and substantia nigra (SN), which are known targets of the etiological noxae in PD and related disorders. LC and SN pars compacta neurons both degenerate in PD and other Parkinsonisms although LC neurons are comparatively less affected with a variable degree of involvement. In this study, iron, copper and their major molecular forms like ferritins, ceruloplasmin, neuromelanin (NM), manganese-superoxide dismutase (SOD) and copper/zinc-SOD were measured in LC and SN of normal subjects at different ages. Iron content in LC was much lower than that in SN and the ratio of heavy chain ferritin / iron in LC was higher than in SN. The NM concentrations were similar in LC and SN although the iron content in NM of LC was much lower than in SN. In both regions, heavy and light chain ferritins were present only in glia and were not detectable in neurons. This data suggests that iron mobilization and toxicity are lower in LC neurons than in SN and are efficiently buffered by NM. The greater damage occuring in SN could be related to the higher content of iron. Ferritins accomplish the same function of buffering iron in glial cells. Ceruloplasmin levels were similar in LC and SN although copper content was higher in LC. However, the copper content in NM of LC was higher than that of SN, indicating a higher copper mobilization in LC neurons. Manganese-SOD and copper / zinc-SOD had similar age-related trends in LC and SN. These results may explain some of the underlying lower vulnerability of LC compared to SN in Parkinsonian syndromes. …