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

Plum, Sarah; Steinbach, Simone; Attems, Johannes; Keers, Sharon; Riederer, Peter; Gerlach, Manfred; May, Caroline; Marcus, Katrin

doi:10.1038/srep37139

Cited by 44 publications

(72 citation statements)

References 34 publications

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“…properties to the melanin found in skin, hair and eyes, being insoluble to organic solvents and labelled by silver stains (58,59), which was why it was called "neuromelanin". However, little is known about the biology and the physiological functions of NM.…”

Section: Discussionmentioning

confidence: 99%

Neurobiological Alterations Of The Substantia Nigra In Sudden Infant Death Syndrome

Lavezzi¹,

Mehboob²,

Alfonsi³

et al. 2020

Preprint

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Background - The purpose of this study was to research possible morphological and functional alterations of the substantia nigra in SIDS. Methods - Brainstems of 46 victims of sudden infant death, aged from 1 to 7 months, were investigated. Twenty-six of these cases were diagnosed as SIDS, due to the lack of any pathological finding, while the remaining 20 cases, in which the cause of death was determined at autopsy, served as controls. Maternal smoking was reported in 10% of controls and 77% of SIDS. Histopathological examination of the substantia nigra was done on midbrain 5-µm-thick sections stained with hematoxylin-eosin and Klüver-Barrera. Densitometry, immunohistochemistry and histochemistry were applied to highlight the neuronal concentration, the expression of tyrosine hydroxylase and neuromelanin, respectively. Results - Hypoplasia of the pars compacta of the substantia nigra was observed in SIDS but not in controls. Tyrosine hydroxylase expression in the substantia nigra was significantly higher in controls than in SIDS. Neuromelanin was observed as dark granules only in 4 infants of the control group but never in SIDS. A significant correlation was found between hypoplasia/low neuronal density, low tyrosine hydroxylase expression in the substantia nigra pars compacta and maternal smoking. Conclusion - The substantia nigra pars compacta, that is the main dopamine center in the brain, is involved in the control of many functions, including the sleep-arousal phase, and hence, its structural and/or functional alterations may explain the pathogenesis of SIDS, that often occurs during sleep. This study also indicates that maternal smoking can may have strongly influenced the SN altered development. Trial registration – not applicable for this study

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Section: Discussionmentioning

confidence: 99%

Neurobiological Alterations Of The Substantia Nigra In Sudden Infant Death Syndrome

Lavezzi¹,

Mehboob²,

Alfonsi³

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…44,45 Similarly, mass spectrometry techniques failed to detect significant amounts of typical enzymes and proteins involved in melanogenesis, including tyrosinase, in isolated neuromelanin-containing organelles from human SN. 15,46,47 In contrast, tyrosinase enzymatic activity has been reported in brain extracts from human SN, 41 although at 100,000 times lower than in melanocytes. 48 These inconsistent results could be potentially attributed to the very low levels at which tyrosinase might be actually expressed, if at all, in the brain and further experiments are thus warranted to unambiguously demonstrate or refute the existence of tyrosinase in the human brain.…”

Section: Synthesis Of Neuromelanin: Mechanisms and Significancementioning

confidence: 92%

“…Consistent with the very low levels at which tyrosinase mRNA might be expressed, if at all, in the brain, the actual protein has not been detected in the human brain when using immunohistochemistry or Western blot . Similarly, mass spectrometry techniques failed to detect significant amounts of typical enzymes and proteins involved in melanogenesis, including tyrosinase, in isolated neuromelanin‐containing organelles from human SN . In contrast, tyrosinase enzymatic activity has been reported in brain extracts from human SN, although at 100,000 times lower than in melanocytes .…”

Section: Synthesis Of Neuromelanin: Mechanisms and Significancementioning

confidence: 99%

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

Vila

2019

Movement Disorders

107

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Neuromelanin, a dark brown intracellular pigment, has long been associated with Parkinson's disease (PD). In PD, neuromelanin‐containing neurons preferentially degenerate, tell‐tale neuropathological inclusions form in close association with this pigment, and neuroinflammation is restricted to neuromelanin‐containing areas. In humans, neuromelanin accumulates with age, which in turn is the main risk factor for PD. The potential contribution of neuromelanin to PD pathogenesis remains unknown because, in contrast to humans, common laboratory animals lack neuromelanin. The recent introduction of a rodent model exhibiting an age‐dependent production of human‐like neuromelanin has allowed, for the first time, for the consequences of progressive neuromelanin accumulation—up to levels reached in elderly human brains—to be assessed in vivo. In these animals, intracellular neuromelanin accumulation above a specific threshold compromises neuronal function and triggers a PD‐like pathology. As neuromelanin levels reach this threshold in PD patients and presymptomatic PD patients, the modulation of neuromelanin accumulation could provide a therapeutic benefit for PD patients and delay brain aging. © 2019 The Author. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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“…Because neuromelanin granules have been found in lysosomes (13), the accumulation of neuromelanin-like aggregates in mutant dopaminergic neurons suggested that lysosomal function might be impaired. While there was no detectable impairment in lysosomal proteolysis in homozygous DJ-1 mutant neurons at d70 (Fig.…”

Section: Dopamine-mediated Modification Of Glucocerebrosidase (Gcase)mentioning

confidence: 99%

Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease

Burbulla

Song

Mazzulli

et al. 2017

Science

678

640

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Mitochondrial and lysosomal dysfunction have been implicated in substantia nigra dopaminergic neurodegeneration in Parkinson’s disease (PD), but how these pathways are linked in human neurons remains unclear. Here we studied dopaminergic neurons derived from patients with idiopathic and familial PD. We identified a time-dependent pathological cascade beginning with mitochondrial oxidant stress leading to oxidized dopamine accumulation and ultimately resulting in reduced glucocerebrosidase enzymatic activity, lysosomal dysfunction, and α-synuclein accumulation. This toxic cascade was observed in human, but not in mouse, PD neurons at least in part because of species-specific differences in dopamine metabolism. Increasing dopamine synthesis or α-synuclein amounts in mouse midbrain neurons recapitulated pathological phenotypes observed in human neurons. Thus, dopamine oxidation represents an important link between mitochondrial and lysosomal dysfunction in PD pathogenesis.

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

Cited by 44 publications

References 34 publications

Neurobiological Alterations Of The Substantia Nigra In Sudden Infant Death Syndrome

Neurobiological Alterations Of The Substantia Nigra In Sudden Infant Death Syndrome

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease

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