Is the Vulnerability of Neurons in the Substantia Nigra of Patients with Parkinson's Disease Related to Their Neuromelanin Content?

Abstract

The contribution of neuromelanin (NM) to the pathogenesis of Parkinson's disease (PD) has long been suspected. In particular, a correlation has been reported between the estimated cell loss in the mesencephalic dopaminergic cell groups and the percentage of NM-pigmented neurons in these cell groups. To test whether the amount of pigment per cell is a critical factor or whether the presence of NM within a neuron is sufficient to account for the degeneration of dopaminergic neurons, the NM content was measured in each neuron from representative sections throughout the ventral mesencephalon of four controls subjects and four patients with PD. Intraneuronal NM was quantified by a densitometric method, using known amounts of synthetic melanin as standards. In control brains, the distribution of melanized neurons in the nigral complex showed a high proportion of lightly melanized neurons in the ventral tegmental area and the pars alpha and gamma of the substantia nigra (SN), whereas heavily melanized neurons were mostly located in the pars beta and lateralis of the SN. An inverse relationship was observed between the percentage of surviving neurons in PD compared with controls and the amount of NM they contain, suggesting that the vulnerability of the dopaminergic neurons is related to their NM content. Factors other than NM may be involved in the differential vulnerability of catecholaminergic neurons in PD. In particular, the constant topography of the cell loss suggests that cell position within the nigral complex is a key factor.

Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking

“…It should be noted that A9 dopaminergic neurons, which contain a high level of α-Syn (48,49) and increased pigmentation by neuromelanin in the early stage of PD before producing Lewy bodies (12,50,51), exhibit early vulnerability. Analysis of brain samples from PD patients showed that the optical density of neuromelanin increased together with α-Syn accumulation around the neuromelanin granules in A9 neurons (51), and α-Syn was found to be a major proteic component, cross-linked to neuromelanin from brains of PD patients (52).…”

Identification of L-ferritin in Neuromelanin Granules of the Human Substantia Nigra

“…Interest in this pigment has seen a resurgence in recent years because of a hypothesized link between NM and the especial vulnerability of NM-containing neurons of the substantia nigra pars compacta (SN) for cell death in Parkinson disease (PD) (2,3). In particular, the interaction between iron and NM has been a focus of research (4 -8) because a marked accumulation of iron related to disease severity is reported in the parkinsonian SN (9 -11).…”

New melanic pigments in the human brain that accumulate in aging and block environmental toxic metals

“…In both of these regions of the human brain, the neuromelanin concentration normally increases linearly with age. In Parkinson's disease, the tissue concentration of neuromelanin decreases dramatically because DA pigmented neurons are preferentially lost compared with nonpigmented ones (3,4). Reduced neuronal content of neuromelanin in substantia nigra has been reported in patients with Parkinson's disease (3), Alzheimer's disease (5), and Rett syndrome (6).…”