scholarly journals Nucleolipid Acid-Based Nanocarriers Restore Neuronal Lysosomal Acidification Defects

2021 ◽  
Vol 9 ◽  
Author(s):  
Mathias Brouillard ◽  
Philippe Barthélémy ◽  
Benjamin Dehay ◽  
Sylvie Crauste-Manciet ◽  
Valérie Desvergnes
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Cell Model ◽  
Biological Assays ◽  
Lysosomal Ph ◽  
Cellular Models ◽  
Oil In Water ◽  
The Central Nervous System ◽  
Lysosomal Acidification

Increasing evidence suggests that lysosomal dysfunction has a pathogenic role in neurodegenerative diseases. In particular, an increase in lysosomal pH has been reported in different cellular models of Parkinson’s disease. Thus, targeting lysosomes has emerged as a promising approach. More specifically, regulating its pH could play a central role against the neurodegeneration process. To date, only a few agents specifically targeting lysosomal pH are reported in the literature, partly due to the challenge of crossing the Blood-Brain-Barrier (BBB), preventing drug penetration into the central nervous system (CNS). To develop chronic treatments for neurodegenerative diseases, crossing the BBB is crucial. We report herein the conception and synthesis of an innovative DNA derivative-based nanocarrier. Nucleolipids, carrying a biocompatible organic acid as an active ingredient, were designed and synthesized as prodrugs. They were successfully incorporated into an oil-in-water nanoemulsion vehicle to cross biological membranes and then release effectively biocompatible acidic components to restore the functional lysosomal pH of neuronal cells. Biological assays on a genetic cell model of Parkinson’s disease highlighted the non-toxicity of such nucleolipids after cellular uptake and their ability (at c = 40 µM) to fully restore lysosomal acidity.

scholarly journals Co-loading of Levodopa and Curcumin Using Brain-targeted Protocells for Improving the Efficacy of Parkinson's Disease

2021 ◽  
Author(s):  
Wenkai Zhou ◽  
Chang Liu ◽  
Feifei Yu ◽  
Xia Niu ◽  
Xiaomei Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inner Core ◽  
Cell Model ◽  
Mesoporous Silica Nanoparticles ◽  
Brain Targeting ◽  
Delivery Platform ◽  
The Central Nervous System ◽  
Nanoparticle System ◽  
Clinical Drug

Abstract Parkinson's disease (PD), one of the most common movement and neurodegenerative disorders, is challenging to treat. Levodopa is a common clinical drug for controlling the symptoms of PD, but it only replenishes the missing dopamine, can’t protect dopaminergic neurons. While curcumin as a neuroprotective agent has been reported for treatment of PD. Herein, we present a novel organic-inorganic composite nanoparticle with brain targeting (lf-protocells) for co-delivery of levodopa and curcumin, and demonstrate its attractive use as a biocompatible platform for PD treatment. The nanoparticle system is comprised of a lactoferrin (lf) modified lipid bilayer (LB) containing curcumin as its outer membrane and mesoporous silica nanoparticles (MSNs) containing levodopa as its supporting inner core. Our studies illustrate that the lf-protocells have a spherical morphology, and can be used to co-load levodopa and curcumin efficiently; the combination of curcumin and levodopa alleviates the apoptosis of PD cells, decreases the expression of a-synuclein and increase the expression of tyrosine hydroxylase in SH-SY5Y cells as compared to single drug; the binary-drug loaded lf-protocells ameliorate oxidative stress and mitochondrial dysfunction as compared to combination of free drugs; lf-protocells improve significantly the distribution in brain compared with unmodified protocells; binary-drug loaded lf-protocells have better performance of motor function in mouse than unmodified protocells and combination of free drugs. In conclusion, binary-drug loaded lf-protocells show better therapeutic efficacy in both cell model and mouse model of PD than combination of free drugs and lower toxicity than bare MSNs. These results suggest that lf-protocells can be used as a promising drug delivery platform for targeted therapy against PD and other diseases of the central nervous system.

scholarly journals A Novel Long-Noncoding RNA LncZFAS1 Prevents MPP+-Induced Neuroinflammation Through MIB1 Activation

2021 ◽  
Author(s):  
Ziman Zhu ◽  
Peiling Huang ◽  
Ruifeng Sun ◽  
Xiaoling Li ◽  
Wenshan Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Noncoding Rna ◽  
Cell Model ◽  
Developed Countries ◽  
Inflammasome Activation ◽  
Transcriptional Regulatory ◽  
Regulatory Functions

AbstractParkinson’s disease remains one of the leading neurodegenerative diseases in developed countries. Despite well-defined symptomology and pathology, the complexity of Parkinson’s disease prevents a full understanding of its etiological mechanism. Mechanistically, α-synuclein misfolding and aggregation appear to be central for disease progression, but mitochondrial dysfunction, dysfunctional protein clearance and ubiquitin/proteasome systems, and neuroinflammation have also been associated with Parkinson’s disease. Particularly, neuroinflammation, which was initially thought to be a side effect of Parkinson’s disease pathogenesis, has now been recognized as driver of Parkinson’s disease exacerbation. Next-generation sequencing has been used to identify a plethora of long noncoding RNAs (lncRNA) with important transcriptional regulatory functions. Moreover, a myriad of lncRNAs are known to be regulators of inflammatory signaling and neurodegenerative diseases, including IL-1β secretion and Parkinson’s disease. Here, LncZFAS1 was identified as a regulator of inflammasome activation, and pyroptosis in human neuroblast SH-SY5Y cells following MPP+ treatment, a common in vitro Parkinson’s disease cell model. Mechanistically, TXNIP ubiquitination through MIB1 E3 ubiquitin ligase regulates NLRP3 inflammasome activation in neuroblasts. In contrast, MPP+ activates the NLPR3 inflammasome through miR590-3p upregulation and direct interference with MIB1-dependent TXNIP ubiquitination. LncZFAS overexpression inhibits this entire pathway through direct interference with miR590-3p, exposing a novel research idea regarding the mechanism of Parkinson’s disease.

scholarly journals Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson’s disease model

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Chunni Zhu ◽  
Tina Bilousova ◽  
Samantha Focht ◽  
Michael Jun ◽  
Chris Jean Elias ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Motor Function ◽  
Cell Model ◽  
Extracellular Vesicle ◽  
Alpha Synuclein ◽  
Proteinase K ◽  
In Vivo Studies

Abstract Aim We have previously reported that cambinol (DDL-112), a known inhibitor of neutral sphingomyelinase-2 (nSMase2), suppressed extracellular vesicle (EV)/exosome production in vitro in a cell model and reduced tau seed propagation. The enzyme nSMase2 is involved in the production of exosomes carrying proteopathic seeds and could contribute to cell-to-cell transmission of pathological protein aggregates implicated in neurodegenerative diseases such as Parkinson’s disease (PD). Here, we performed in vivo studies to determine if DDL-112 can reduce brain EV/exosome production and proteopathic alpha synuclein (αSyn) spread in a PD mouse model. Methods The acute effects of single-dose treatment with DDL-112 on interleukin-1β-induced extracellular vesicle (EV) release in brain tissue of Thy1-αSyn PD model mice and chronic effects of 5 week DDL-112 treatment on behavioral/motor function and proteinase K-resistant αSyn aggregates in the PD model were determined. Results/discussion In the acute study, pre-treatment with DDL-112 reduced EV/exosome biogenesis and in the chronic study, treatment with DDL-112 was associated with a reduction in αSyn aggregates in the substantia nigra and improvement in motor function. Inhibition of nSMase2 thus offers a new approach to therapeutic development for neurodegenerative diseases with the potential to reduce the spread of disease-specific proteopathic proteins.

scholarly journals A novel Long-noncoding RNA LncZFAS1 prevents MPP+-induced neuroinflammation through MIB1 activation

2021 ◽  
Author(s):  
Ziman Zhu ◽  
Peiling Huang ◽  
Ruifeng Sun ◽  
Xiaoling Li ◽  
Wenshan Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Noncoding Rna ◽  
Cell Model ◽  
Developed Countries ◽  
Inflammasome Activation ◽  
Transcriptional Regulatory ◽  
Regulatory Functions

Abstract Parkinson’s disease remains one of the leading neurodegenerative diseases in developed countries. Despite well-defined symptomology and pathology, the complexity of Parkinson’s disease prevents a full understanding of its’ etiological mechanism. Mechanistically, α-synuclein misfolding and aggregation appears central for disease progression, but mitochondrial dysfunction, dysfunctional protein clearance and ubiquitin/proteasome systems, and neuroinflammation have also been associated with Parkinson’s disease. Particularly neuroinflammation, which was initially thought to be a side effect of Parkinson’s disease pathogenesis, has now been recognized as driver of Parkinson’s disease exacerbation. Next-generation sequencing identified a plethora of long noncoding RNAs (lncRNA) with important transcriptional regulatory functions. Moreover, a myriad of lncRNA are known regulators of inflammatory signaling and neurodegenerative diseases including IL-1β secretion and Parkinson’s disease. Here lncZFAS1 was identified as a regulator of inflammasome activation and pyroptosis in human neuroblast SH-SY5Y cells following MPP+ treatment, a common in vitro Parkinson’s disease cell model. Mechanistically, TXNIP ubiquitination through MIB1 E3 ubiquitin ligase regulates NLRP3 inflammasome activation in neuroblast cells. In contrast MPP+ activates the NLPR3 inflammasome through miR590-3p up-regulation, and direct interference with MIB1-dependent TXNIP ubiquitination. LncZFAS overexpression inhibits this entire pathway through direct interference with miR590-3p exposing a novel therapeutic target to prevent excessive inflammasome activation and pyroptosis in neuroblast cells during Parkinson's disease.

scholarly journals A novel Long-noncoding RNA LncZFAS1 prevents MPP+-induced neuroinflammation through MIB1 activation

2021 ◽  
Author(s):  
Ziman Zhu ◽  
Peiling Huang ◽  
Ruifeng Sun ◽  
Xiaoling Li ◽  
Wenshan Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Noncoding Rna ◽  
Cell Model ◽  
Developed Countries ◽  
Inflammasome Activation ◽  
Transcriptional Regulatory ◽  
Regulatory Functions

Abstract Parkinson’s disease remains one of the leading neurodegenerative diseases in developed countries. Despite well-defined symptomology and pathology, the complexity of Parkinson’s disease prevents a full understanding of its’ etiological mechanism. Mechanistically, α-synuclein misfolding and aggregation appears central for disease progression, but mitochondrial dysfunction, dysfunctional protein clearance and ubiquitin/proteasome systems, and neuroinflammation have also been associated with Parkinson’s disease. Particularly neuroinflammation, which was initially thought to be a side effect of Parkinson’s disease pathogenesis, has now been recognized as driver of Parkinson’s disease exacerbation. Next-generation sequencing identified a plethora of long noncoding RNAs (lncRNA) with important transcriptional regulatory functions. Moreover, a myriad of lncRNA are known regulators of inflammatory signaling and neurodegenerative diseases including IL-1β secretion and Parkinson’s disease. Here lncZFAS1 was identified as a regulator of inflammasome activation and pyroptosis in human neuroblast SH-SY5Y cells following MPP+ treatment, a common in vitro Parkinson’s disease cell model. Mechanistically, TXNIP ubiquitination through MIB1 E3 ubiquitin ligase regulates NLRP3 inflammasome activation in neuroblast cells. In contrast MPP+ activates the NLPR3 inflammasome through miR590-3p up-regulation, and direct interference with MIB1-dependent TXNIP ubiquitination. LncZFAS overexpression inhibits this entire pathway through direct interference with miR590-3p exposing a novel therapeutic target to prevent excessive inflammasome activation and pyroptosis in neuroblast cells during Parkinson's disease.

Neuroprotective Effect of Coptis chinensis in MPP+ and MPTP-Induced Parkinson’s Disease Models

2016 ◽  
Vol 44 (05) ◽  
pp. 907-925 ◽  
Author(s):  
Thomas Friedemann ◽  
Yue Ying ◽  
Weigang Wang ◽  
Edgar R. Kramer ◽  
Udo Schumacher ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Cell Model ◽  
Neuroprotective Effect ◽  
Treatment Options ◽  
Coptis Chinensis

The rhizome of Coptis chinensis is commonly used in traditional Chinese medicine alone or in combination with other herbs to treat diseases characterized by causing oxidative stress including inflammatory diseases, diabetes mellitus and neurodegenerative diseases. In particular, there is emerging evidence that Coptis chinensis is effective in the treatment of neurodegenerative diseases associated with oxidative stress. Hence, the aim of this study was to investigate the neuroprotective effect of Coptis chinensis in vitro and in vivo using MPP[Formula: see text] and MPTP models of Parkinson’s disease. MPP[Formula: see text] treated human SH-SY5Y neuroblastoma cells were used as a cell model of Parkinson’s disease. A 24[Formula: see text]h pre-treatment of the cells with the watery extract of Coptis chinensis significantly increased cell viability, as well as the intracellular ATP concentration and attenuated apoptosis compared to the MPP[Formula: see text] control. Further experiments with the main alkaloids of Coptidis chinensis, berberine, coptisine, jaterorrhizine and palmatine revealed that berberine and coptisine were the main active compounds responsible for the observed neuroprotective effect. However, the full extract of Coptis chinensis was more effective than the tested single alkaloids. In the MPTP-induced animal model of Parkinson’s disease, Coptis chinensis dose-dependently improved motor functions and increased tyrosine hydroxylase-positive neurons in the substantia nigra compared to the MPTP control. Based on the results of this work, Coptis chinensis and its main alkaloids could be considered potential candidates for the development of new treatment options for Parkinson’s disease.

scholarly journals Hypoxia, Acidification and Inflammation: Partners in Crime in Parkinson’s Disease Pathogenesis?

Immuno ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 78-90
Author(s):  
Johannes Burtscher ◽  
Grégoire P. Millet
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Current Knowledge ◽  
Cell Types ◽  
Brain Cell ◽  
Special Focus ◽  
Molecular Alterations ◽  
Research Fields

Like in other neurodegenerative diseases, protein aggregation, mitochondrial dysfunction, oxidative stress and neuroinflammation are hallmarks of Parkinson’s disease (PD). Differentiating characteristics of PD include the central role of α-synuclein in the aggregation pathology, a distinct vulnerability of the striato-nigral system with the related motor symptoms, as well as specific mitochondrial deficits. Which molecular alterations cause neurodegeneration and drive PD pathogenesis is poorly understood. Here, we summarize evidence of the involvement of three interdependent factors in PD and suggest that their interplay is likely a trigger and/or aggravator of PD-related neurodegeneration: hypoxia, acidification and inflammation. We aim to integrate the existing knowledge on the well-established role of inflammation and immunity, the emerging interest in the contribution of hypoxic insults and the rather neglected effects of brain acidification in PD pathogenesis. Their tight association as an important aspect of the disease merits detailed investigation. Consequences of related injuries are discussed in the context of aging and the interaction of different brain cell types, in particular with regard to potential consequences on the vulnerability of dopaminergic neurons in the substantia nigra. A special focus is put on the identification of current knowledge gaps and we emphasize the importance of related insights from other research fields, such as cancer research and immunometabolism, for neurodegeneration research. The highlighted interplay of hypoxia, acidification and inflammation is likely also of relevance for other neurodegenerative diseases, despite disease-specific biochemical and metabolic alterations.

scholarly journals The Baseline Structure of the Enteric Nervous System and Its Role in Parkinson’s Disease

Life ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 732
Author(s):  
Gianfranco Natale ◽  
Larisa Ryskalin ◽  
Gabriele Morucci ◽  
Gloria Lazzeri ◽  
Alessandro Frati ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nervous System ◽  
Enteric Nervous System ◽  
Gi Tract ◽  
Multiple Control ◽  
Fine Control ◽  
The Central Nervous System ◽  
Degenerative Alterations ◽  
Comprehensive Classification

The gastrointestinal (GI) tract is provided with a peculiar nervous network, known as the enteric nervous system (ENS), which is dedicated to the fine control of digestive functions. This forms a complex network, which includes several types of neurons, as well as glial cells. Despite extensive studies, a comprehensive classification of these neurons is still lacking. The complexity of ENS is magnified by a multiple control of the central nervous system, and bidirectional communication between various central nervous areas and the gut occurs. This lends substance to the complexity of the microbiota–gut–brain axis, which represents the network governing homeostasis through nervous, endocrine, immune, and metabolic pathways. The present manuscript is dedicated to identifying various neuronal cytotypes belonging to ENS in baseline conditions. The second part of the study provides evidence on how these very same neurons are altered during Parkinson’s disease. In fact, although being defined as a movement disorder, Parkinson’s disease features a number of degenerative alterations, which often anticipate motor symptoms. Among these, the GI tract is often involved, and for this reason, it is important to assess its normal and pathological structure. A deeper knowledge of the ENS is expected to improve the understanding of diagnosis and treatment of Parkinson’s disease.

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