Evidence for specific phases in the development of human neuromelanin

Abstract

Neuromelanin is a dark-coloured pigment which forms in the dopamine neurons of the human midbrain. Here we describe the age-related development and regulation of neuromelanin within these dopamine neurons. 10 microm sections from formalin-fixed midbrain from 29 people spanning the ages of 24 weeks to 95 years old were either stained with a basic Nissl substance stain (0.5% cresyl violet), or processed unstained. After locating the substantia nigra using the stained sections, digital photos were taken of individual ventral substantia nigra neurons in the unstained sections, and the cellular area occupied by pigment, and optical density were measured using computer software. These measurements demonstrated three developmental phases. Neuromelanin was not present at birth and initiation of pigmentation began at approximately 3 years of age, followed by a period of increasing pigment granule number and increasing pigment granule colouration until age 20. In middle and later life the colour of the pigment granules continued to darken but was not associated with any substantial growth in pigment volume. The identification of three phases and changes in the rate of neuromelanin production over time suggests the regulation of neuromelanin production and turnover, possibly through enzymatic processes.

Proteomic characterization of neuromelanin granules isolated from human substantia nigra by laser-microdissection

“…By utilization of the Gene Ontology annotations 19 proteins of the differentially expressed proteins could be related to lysosomes, which underlines the lysosomal relationship of NM granule which was already previously described37. Previously knowledge23 combined with these new findings lead to the hypothetical process describing NM granules genesis depicted in Fig. 3.…”

“…So far NM granules cannot be identified in human newborns, but seem to start forming in childhood presumably from the age of three years. From then on an increase in amount and density of NM granules can be observed during normal aging23. The physiological function of NM granules is controversial discussed in literature.…”

Parkinson's disease as a result of aging

“…PD showed a decrease in nigral pigmented neurons (Hirsch et al ., 1988, 1989; Fearnley & Lees, 1991), which suggested that the selective degeneration of these cells could be a feature of this illness and that neuromelanin may be involved in this degeneration (Hirsch et al ., 1988). However, healthy aged subjects also showed a decrease in pigmented cells (7-10% decrease per decade) (McGeer et al ., 1988; Ma et al ., 1999; Cabello et al ., 2002; Stark & Pakkenberg, 2004; Fedorow et al ., 2005; Halliday et al ., 2006; Double et al ., 2008; Rudow et al ., 2008), suggesting that if neuromelanin was involved in PD, it could also be involved in aging-related neurodegeneration.…”

Histologic validation of locus coeruleus MRI contrast in post-mortem tissue

“…Neuromelanin is a byproduct of neuronal norepinephrine (NE) and dopamine synthesis, accumulating in cell bodies beginning in early childhood and increasing in concentration throughout life (Zecca et al, 2004; Halliday et al, 2006). Thus, neuromelanin is a target for biomarker development to characterize neurodegenerative diseases where low contrast is predicted to occur with LC neuron loss in older adult samples.…”