In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 97, No. 22 ( 2000-10-24), p. 11869-11874
Abstract:
Melanin, the pigment in hair, skin, eyes, and feathers, protects
external tissue from damage by UV light. In contrast, neuromelanin (NM)
is found in deep brain regions, specifically in loci that degenerate in Parkinson's disease. Although this distribution suggests a role for NM
in Parkinson's disease neurodegeneration, the biosynthesis and function of NM have eluded characterization because of lack of an
experimental system. We induced NM in rat substantia nigra and PC12 cell cultures by exposure to l -dihydroxyphenylalanine,
which is rapidly converted to dopamine (DA) in the cytosol. This pigment was identical to human NM as assessed by paramagnetic resonance
and was localized in double membrane autophagic vacuoles identical to NM granules of human substantia nigra. NM synthesis was abolished by
adenoviral-mediated overexpression of the synaptic vesicle catecholamine transporter VMAT2, which decreases cytosolic DA by
increasing vesicular accumulation of neurotransmitter. The NM is in a stable complex with ferric iron, and NM synthesis was inhibited by the
iron chelator desferrioxamine, indicating that cytosolic DA and dihydroxyphenylalanine are oxidized by iron-mediated catalysis to
membrane-impermeant quinones and semiquinones. NM synthesis thus results from excess cytosolic catecholamines not accumulated into
synaptic vesicles. The permanent accumulation of excess catechols, quinones, and catechol adducts into a membrane-impermeant substance
trapped in organelles may provide an antioxidant mechanism for catecholamine neurons. However, NM in organelles associated with
secretory pathways may interfere with signaling, as it delays stimulated neurite outgrowth in PC12 cells.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.97.22.11869
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2000
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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