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

Vila, Miquel

doi:10.1002/mds.27776

Cited by 107 publications

(86 citation statements)

References 102 publications

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“…Neurochemical content and receptor expression are also very heterogeneous containing adrenergic, GABAergic, serotonergic, glutamatergic, µ-opioid, orexin/hypocreatin, nicotinic acetylcholine, and cannabinoid receptors (reviewed in Berridge and Waterhouse, 2003;Schwarz and Luo, 2015). LC noradrenergic cells, as happens with SNc neurons, also contains neuromelanin which makes them specially vulnerable to neurodegeneration in PD (reviewed in Martin-Bastida et al, 2017 andVila, 2019).…”

Section: The Locus Coeruleusmentioning

confidence: 99%

The Noradrenergic System in Parkinson’s Disease

et al. 2020

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Nowadays it is well accepted that in Parkinson's disease (PD), the neurodegenerative process occurs in stages and that damage to other areas precedes the neuronal loss in the substantia nigra pars compacta, which is considered a pathophysiological hallmark of PD. This heterogeneous and progressive neurodegeneration may explain the diverse symptomatology of the disease, including motor and non-motor alterations. In PD, one of the first areas undergoing degeneration is the locus coeruleus (LC). This noradrenergic nucleus provides extensive innervation throughout the brain and plays a fundamental neuromodulator role, participating in stress responses, emotional memory, and control of motor, sensory, and autonomic functions. Early in the disease, LC neurons suffer modifications that can condition the effectiveness of pharmacological treatments, and importantly, can lead to the appearance of common non-motor symptomatology. The noradrenergic system also exerts anti-inflammatory and neuroprotective effect on the dopaminergic degeneration and noradrenergic damage can consequently condition the progress of the disease. From the pharmacological point of view, it is also important to understand how the noradrenergic system performs in PD, since noradrenergic medication is often used in these patients, and drug interactions can take place when combining them with the gold standard drug therapy in PD, L-3,4-dihydroxyphenylalanine (L-DOPA). This review provides an overview about the functional status of the noradrenergic system in PD and its contribution to the efficacy of pharmacologicalbased treatments. Based on preclinical and clinical publications, a special attention will be dedicated to the most prevalent non-motor symptoms of the disease.

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Section: The Locus Coeruleusmentioning

confidence: 99%

The Noradrenergic System in Parkinson’s Disease

et al. 2020

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“…Therefore, a more comprehensive investigation of the links between neuromelanin, heavy metal content, and LC susceptibility to developing neuropathology or degeneration is warranted. Interestingly, although the LC develops pathology decades prior to clinical onset, it is relatively spared from degeneration until clinical presentation, which suggests that neuromelanin accumulation may work in concert with neuropathology to trigger neurodegeneration ( Weinshenker, 2018 ; Vila, 2019 ). Specifically, neuromelanin sequesters catecholamine metabolites, and the noradrenergic-specific metabolite DOPEGAL can trigger tau cleavage, hyperphosphorylation, and LC degeneration ( Weinshenker, 2018 ; Kang et al, 2020 ).…”

Section: Human Studiesmentioning

confidence: 99%

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

Kelberman

Keilholz

2020

Front. Neurosci.

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The locus coeruleus (LC) has long been underappreciated for its role in the pathophysiology of Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative disorders. While AD and PD are distinct in clinical presentation, both are characterized by prodromal protein aggregation in the LC, late-stage degeneration of the LC, and comorbid conditions indicative of LC dysfunction. Many of these early studies were limited to post-mortem histological techniques due to the LC’s small size and location deep in the brainstem. Thus, there is a growing interest in utilizing in vivo imaging of the LC as a predictor of preclinical neurodegenerative processes and biomarker of disease progression. Simultaneously, neuroimaging in animal models of neurodegenerative disease holds promise for identifying early alterations to LC circuits, but has thus far been underutilized. While still in its infancy, a handful of studies have reported effects of single gene mutations and pathology on LC function in disease using various neuroimaging techniques. Furthermore, combining imaging and optogenetics or chemogenetics allows for interrogation of network connectivity in response to changes in LC activity. The purpose of this article is twofold: (1) to review what magnetic resonance imaging (MRI) and positron emission tomography (PET) have revealed about LC dysfunction in neurodegenerative disease and its potential as a biomarker in humans, and (2) to explore how animal models can be used to test hypotheses derived from clinical data and establish a mechanistic framework to inform LC-focused therapeutic interventions to alleviate symptoms and impede disease progression.

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“…Melanin, one of the most ubiquitous and stable biopolymers, is produced in living organisms by a particular group of cells called melanocytes [ 1 , 2 , 3 ]. It is found in the organs of almost every higher-level organism, including human skin [ 4 ], hair [ 5 ], eyes [ 6 ], and the brain [ 7 ]. And occurs in different forms including eumelanin (a black-brownish pigment), pheomelanin (a red pigment), and neuromelanin (which is generated by dopaminergic neurons in the brain) [ 1 , 2 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is found in the organs of almost every higher-level organism, including human skin [ 4 ], hair [ 5 ], eyes [ 6 ], and the brain [ 7 ]. And occurs in different forms including eumelanin (a black-brownish pigment), pheomelanin (a red pigment), and neuromelanin (which is generated by dopaminergic neurons in the brain) [ 1 , 2 , 7 ]. Its functionality is defined (although not fully understood) by its physical and chemical properties, such as its featureless broad optical absorption, antioxidant properties, and free radical scavenging behavior [ 1 , 2 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Inkjet Printing of Synthesized Melanin Nanoparticles as a Biocompatible Matrix for Pharmacologic Agents

et al. 2020

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Melanin is a natural biopigment that is produced by melanocytes and can be found in most living organisms. The unique physical and chemical properties of melanin render it potentially useful for numerous applications, particularly those in which a biocompatible functional material is required. Herein, we introduce one important technology in which melanin can be utilized: a drug delivery system in terms of a biocompatible matrix. However, extracting melanin from different biological sources is costly and time-consuming and introduces variabilities in terms of chemical structure, properties, and functions. Hence, a functionally reproducible system is hard to achieve using biologically extracted melanin. Here we report the synthesis of melanin nanoparticles of controlled uniform sizes and chemical characteristics. The optical, chemical, and structural characteristics of synthesized nanoparticles were characterized by optical confocal photoluminescence (PL) imaging, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and Zeta potentiometry. The melanin nanoparticles have 100 nm size and a narrow size distribution. The advantage of a nanoparticle structure is its enhanced surface-to-volume ratio compared to bulk pigments, which is important for applications in which controlling the microscopic surface area is essential. Using the inkjet printing technique, we developed melanin thin films with minimum ink waste and loaded them with methylene blue (our representative drug) to test the drug-loading ability of the melanin nanoparticles. Inkjet printing allowed us to create smooth uniform films with precise deposition and minimum ink-waste. The spectroscopic analysis confirmed the attachment of the “drug” onto the melanin nanoparticles as a matrix. Hence, our data identify melanin as a material system to integrate into drug release applications.

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

Cited by 107 publications

References 102 publications

The Noradrenergic System in Parkinson’s Disease

The Noradrenergic System in Parkinson’s Disease

What’s That (Blue) Spot on my MRI? Multimodal Neuroimaging of the Locus Coeruleus in Neurodegenerative Disease

Inkjet Printing of Synthesized Melanin Nanoparticles as a Biocompatible Matrix for Pharmacologic Agents

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