Residual substantia nigra neuromelanin in Parkinson's disease is cross-linked to alpha-synuclein.
The pigmentation of substantia nigra pars compacta dopaminergic neurons is due to the presence of neuromelanin, an irregular macromolecular pigment belonging to the family of melanins. Depletion of neuromelanin in Parkinson's disease is typically indicated by loss of brown color in this area. Unlike that from controls, the pigment extracted from substantia nigra of parkinsonian patients seems to be mainly composed by highly cross-linked, protease-resistant proteic material and the neuromelanin macromolecule appears to be a minor presence. In the present paper we describe the isolation by SDS-PAGE of this proteic component after cleavage of the melanin backbone under solubilizing conditions. A single band is observed, which has been identified as alpha-synuclein by western blotting. As expected, the same process performed on a control specimen did not show occurrence of any major proteic component. Nevertheless, extraction from a 91 years old control with Lewy bodies displayed minor alpha-synuclein immunoreactive aggregates, whereas inclusion of free alpha-synuclein was not observed at all. Results reported here support the view that alpha-synuclein accumulates within substantia nigra neurons and is entrapped in pigment granules during neuromelanin biosynthesis, i.e. before the melanin depletion characteristic of Parkinson's disease starts.
Fasano
Mauro
M
Department of Structural and Functional Biology, University of Insubria, Via Jean H. Dunant 3, I-21100 Varese, Italy. mauro.fasano@uninsubria.it
Giraudo
Sabrina
S
Coha
Silvia
S
Bergamasco
Bruno
B
Lopiano
Leonardo
L
D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008543:Melanins / Q000737:chemistry*; D009419:Nerve Tissue Proteins / Q000302:isolation & purification*; D010300:Parkinson Disease / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism*; D051843:Synucleins; D051844:alpha-Synuclein
D008543:Melanins; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein; C014121:neuromelanin