α-Synuclein redistributes to neuromelanin lipid in the substantia nigra early in Parkinson's disease

Abstract

The distribution and tempo of neuronal loss in Parkinson's disease correlates poorly with the characteristic and more widely spread intracellular changes associated with the disease process (Lewy bodies and Lewy neurites). To determine early intracellular changes in regions where cell loss is most marked (dopaminergic A9 substantia nigra) versus regions with Lewy bodies but where cell loss is limited, we assessed 13 patients with definite Parkinson's disease at various disease stages in comparison with controls. Using immunohistochemistry for alpha-synuclein, we confirmed the concentration of this protein in the soma of normal A9 neurons and in Lewy body pathology in brainstem catecholamine neurons in Parkinson's disease. Analysis of the degree of cell loss in brainstem catecholamine cell groups revealed that only the A9 substantia nigra had consistent significant cell loss early in the disease course with greater A9 cell loss correlating with increasing disease duration. To assess the earliest intracellular changes differentiating neurons more likely to degenerate, pigmented A9 and A10 neurons with and without obvious pathology were targeted, cell size and pigment density measured, and intracellular changes in alpha-synuclein location and lipid components analysed at both the light and electron microscope levels. There were no changes observed in healthy A10 neurons in Parkinson's disease compared with controls. Pigmented A9 neurons in later stages of degeneration with obvious Lewy body formation had a significant reduction in intracellular pigment, as previously described. In contrast, A9 neurons of normal morphological appearance and no characteristic pathology in Parkinson's disease exhibited significantly increased pigment density associated with a concentration of alpha-synuclein to the lipid component of the pigment and a loss of associated cholesterol. These changes in vulnerable but apparently healthy A9 neurons occurred without any change in cell size or in the amount of intracellular pigment compared with controls. The increase in pigment density is consistent with previously reported increases associated with oxidation and iron loading, reactions known to precipitate alpha-synuclein. The selectivity of the changes observed in A9 nigral neurons suggests that these early intracellular changes predispose these neurons to more rapid cell loss in Parkinson's disease. The increased concentration of neuronal alpha-synuclein and pigment in normal A9 neurons may already predispose these neurons to precipitate alpha-synuclein around pigment-associated lipid under oxidative conditions. Overall, these changes may trigger a cascade of events leading to larger intracellular aggregates of alpha-synuclein and the dispersement of protective pigment to precipitate cell death in Parkinson's disease.

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).…”

“…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). These observations showed that the enhanced dopamine oxidation and the high level of α-Syn are specific features of A9 neurons, which provide favorable environments for the generation of large α-Syn oligomers (17).…”

Evaluation of Parkinson Disease and Alzheimer Disease with the Use of Neuromelanin MR Imaging and123I-Metaiodobenzylguanidine Scintigraphy

“…Noradrenergic neurons are relatively well preserved in the LC of patients with early PD, and they undergo different intracellular changes from the SNc. 20 Reports indicate that the signal intensity of the LC on NmMRI is significantly reduced in PD. 8 We identified significant signal reductions in the LC of patients with late PD, which suggests that lesions emerge in the LC during late PD.…”

Anticipatory postural adjustments stabilise the whole upper-limb prior to a gentle index finger tap

“…However, Lewy pathology can correlate poorly with neuronal loss in specific areas, thus its validity in predicting neuronal disintegration is questionable [29]. In fact, noradrenergic neurons in the LC are relatively preserved in early PD and do not exhibit the same intracellular changes as in the substantia nigra [30].…”