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1.
Nat Commun ; 12(1): 5999, 2021 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-34650037

RESUMEN

Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo protein folding and preventing amyloid formation. Chaperones of the Hsp70 family can further disaggregate otherwise irreversible aggregate species such as α-synuclein fibrils, which accumulate in Parkinson's disease. However, the mechanisms and kinetics of this key functionality are only partially understood. Here, we combine microfluidic measurements with chemical kinetics to study α-synuclein disaggregation. We show that Hsc70 together with its co-chaperones DnaJB1 and Apg2 can completely reverse α-synuclein aggregation back to its soluble monomeric state. This reaction proceeds through first-order kinetics where monomer units are removed directly from the fibril ends with little contribution from intermediate fibril fragmentation steps. These findings extend our mechanistic understanding of the role of chaperones in the suppression of amyloid proliferation and in aggregate clearance, and inform on possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies.


Asunto(s)
Proteínas del Choque Térmico HSC70/metabolismo , Chaperonas Moleculares/metabolismo , alfa-Sinucleína/metabolismo , Amiloide/metabolismo , Escherichia coli , Proteínas del Choque Térmico HSC70/genética , Proteínas del Choque Térmico HSP40 , Proteínas HSP70 de Choque Térmico/metabolismo , Humanos , Cinética , Enfermedad de Parkinson/metabolismo
2.
J Cell Sci ; 134(19)2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34612485

RESUMEN

Mitochondria, which resemble their α-proteobacteria ancestors, are a major cellular asset, producing energy 'on the cheap' through oxidative phosphorylation. They are also a liability. Increased oxidative phosphorylation means increased oxidative stress, and damaged mitochondria incite inflammation through release of their bacteria-like macromolecules. Mitophagy (the selective macroautophagy of mitochondria) controls mitochondria quality and number to manage these risky assets. Parkin, BNIP3 and NIX were identified as being part of the first mitophagy pathways identified in mammals over a decade ago, with additional pathways, including that mediated by FUNDC1 reported more recently. Loss of Parkin or PINK1 function causes Parkinson's disease, highlighting the importance of mitophagy as a quality control mechanism in the brain. Additionally, mitophagy is induced in idiopathic Parkinson's disease and Alzheimer's disease, protects the heart and other organs against energy stress and lipotoxicity, regulates metabolism by controlling mitochondrial number in brown and beige fat, and clears mitochondria during terminal differentiation of glycolytic cells, such as red blood cells and neurons. Despite its importance in disease, mitophagy is likely dispensable under physiological conditions. This Review explores the in vivo roles of mitophagy in mammalian systems, focusing on the best studied examples - mitophagy in neurodegeneration, cardiomyopathy, metabolism, and red blood cell development - to draw out common themes.


Asunto(s)
Mitofagia , Enfermedad de Parkinson , Animales , Mitocondrias/metabolismo , Neuronas/metabolismo , Estrés Oxidativo , Enfermedad de Parkinson/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
3.
Nat Commun ; 12(1): 5907, 2021 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-34625559

RESUMEN

Parkinson's disease and related synucleinopathies are characterized by the abnormal accumulation of alpha-synuclein aggregates, loss of dopaminergic neurons, and gliosis of the substantia nigra. Although clinical evidence and in vitro studies indicate disruption of the Blood-Brain Barrier in Parkinson's disease, the mechanisms mediating the endothelial dysfunction is not well understood. Here we leveraged the Organs-on-Chips technology to develop a human Brain-Chip representative of the substantia nigra area of the brain containing dopaminergic neurons, astrocytes, microglia, pericytes, and microvascular brain endothelial cells, cultured under fluid flow. Our αSyn fibril-induced model was capable of reproducing several key aspects of Parkinson's disease, including accumulation of phosphorylated αSyn (pSer129-αSyn), mitochondrial impairment, neuroinflammation, and compromised barrier function. This model may enable research into the dynamics of cell-cell interactions in human synucleinopathies and serve as a testing platform for target identification and validation of novel therapeutics.


Asunto(s)
Barrera Hematoencefálica/metabolismo , Encéfalo/metabolismo , Enfermedad de Parkinson/metabolismo , Sinucleinopatías/metabolismo , alfa-Sinucleína/metabolismo , Astrocitos/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Neuronas Dopaminérgicas/metabolismo , Células Endoteliales/metabolismo , Gliosis/patología , Humanos , Microglía/metabolismo , Mitocondrias/metabolismo , Pericitos/metabolismo , Fosforilación , Sustancia Negra/metabolismo , Transcriptoma
4.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-34638579

RESUMEN

Parkinson's disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin-proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.


Asunto(s)
Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Cevanas/farmacología , Enfermedad de Parkinson/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , alfa-Sinucleína/metabolismo , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/metabolismo , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Degeneración Nerviosa/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Sustancia Negra/metabolismo , Ubiquitina/metabolismo
5.
Bioessays ; 43(11): e2100168, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34617288

RESUMEN

PTEN-induced kinase 1 (PINK1) is a Parkinson's disease gene that acts as a sensor for mitochondrial damage. Its best understood role involves phosphorylating ubiquitin and the E3 ligase Parkin (PRKN) to trigger a ubiquitylation cascade that results in selective clearance of damaged mitochondria through mitophagy. Here we focus on other physiological roles of PINK1. Some of these also lie upstream of Parkin but others represent autonomous functions, for which alternative substrates have been identified. We argue that PINK1 orchestrates a multi-arm response to mitochondrial damage that impacts on mitochondrial architecture and biogenesis, calcium handling, transcription and translation. We further discuss a role for PINK1 in immune signalling co-ordinated at mitochondria and consider the significance of a freely diffusible cleavage product, that is constitutively generated and degraded under basal conditions.


Asunto(s)
Enfermedad de Parkinson , Proteínas Quinasas , Humanos , Mitocondrias/genética , Mitocondrias/metabolismo , Mitofagia , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Proteínas Quinasas/genética , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitinación
6.
Molecules ; 26(19)2021 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-34641332

RESUMEN

L-DOPA therapy in Parkinson's disease (PD) is limited due to emerging L-DOPA-induced dyskinesia. Research has identified abnormal dopamine release from serotonergic (5-HT) terminals contributing to this dyskinesia. Selective serotonin reuptake inhibitors (SSRIs) or 5-HT receptor (5-HTr) agonists can regulate 5-HT activity and attenuate dyskinesia, but they often also produce a loss of the antiparkinsonian efficacy of L-DOPA. We investigated vilazodone, a novel multimodal 5-HT agent with SSRI and 5-HTr1A partial agonist properties, for its potential to reduce dyskinesia without interfering with the prokinetic effects of L-DOPA, and underlying mechanisms. We assessed vilazodone effects on L-DOPA-induced dyskinesia (abnormal involuntary movements, AIMs) and aberrant responsiveness to corticostriatal drive in striatal medium spiny neurons (MSNs) measured with in vivo single-unit extracellular recordings, in the 6-OHDA rat model of PD. Vilazodone (10 mg/kg) suppressed all subtypes (axial, limb, orolingual) of AIMs induced by L-DOPA (5 mg/kg) and the increase in MSN responsiveness to cortical stimulation (shorter spike onset latency). Both the antidyskinetic effects and reversal in MSN excitability by vilazodone were inhibited by the 5-HTr1A antagonist WAY-100635, demonstrating a critical role for 5-HTr1A in these vilazodone actions. Our results indicate that vilazodone may serve as an adjunct therapeutic for reducing dyskinesia in patients with PD.


Asunto(s)
Discinesia Inducida por Medicamentos/prevención & control , Levodopa/administración & dosificación , Oxidopamina/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Receptor de Serotonina 5-HT1A/metabolismo , Clorhidrato de Vilazodona/administración & dosificación , Animales , Cuerpo Estriado/efectos de los fármacos , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/metabolismo , Regulación de la Expresión Génica , Levodopa/efectos adversos , Masculino , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Clorhidrato de Vilazodona/farmacología
7.
PLoS One ; 16(10): e0252635, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34613964

RESUMEN

Accumulation of aggregated alpha-synuclein (α-syn) is believed to play a pivotal role in the pathophysiology of Parkinson's disease (PD) and other synucleinopathies. As a key constituent of Lewy pathology, more than 90% of α-syn in Lewy bodies is phosphorylated at serine-129 (pS129) and hence, it is used extensively as a marker for α-syn pathology. However, the exact role of pS129 remains controversial and the kinase(s) responsible for the phosphorylation have yet to be determined. In this study, we investigated the effect of Polo-like kinase 2 (PLK2) inhibition on formation of pS129 using an ex vivo organotypic brain slice model of synucleinopathy. Our data demonstrated that PLK2 inhibition has no effect on α-syn aggregation, pS129 or inter-neuronal spreading of the aggregated α-syn seen in the organotypic slices. Instead, PLK2 inhibition reduced the soluble pS129 level in the nuclei. The same finding was replicated in an in vivo mouse model of templated α-syn aggregation and in human dopaminergic neurons, suggesting that PLK2 is more likely to be involved in S129-phosphorylation of the soluble physiological fraction of α-syn. We also demonstrated that reduction of nuclear pS129 following PLK2 inhibition for a short time before sample collection improves the signal-to-noise ratio when quantifying pS129 aggregate pathology.


Asunto(s)
Fosforilación/fisiología , Agregado de Proteínas/fisiología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Serina/metabolismo , alfa-Sinucleína/metabolismo , Animales , Encéfalo/metabolismo , Dopamina/metabolismo , Cuerpos de Lewy/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Enfermedad de Parkinson/metabolismo
8.
Cells ; 10(10)2021 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-34685771

RESUMEN

Parkinson's disease (PD) is a neurodegenerative disorder classified by the loss of dopaminergic neurons in the substantia nigra pars compacta, the region of the brain that is responsible for motor control. Surviving neurons in this region contain aggregated protein alpha-Synuclein (αSyn) in the form of cytoplasmic inclusions, referred to as Lewy bodies. Changes in αSyn expression are also associated with PD and its progression. Previously, we demonstrated that signal recognition particle (SRP) and Argonaute 2 (AGO2) proteins are involved in protein quality control at the ribosome during translation. We also demonstrated that SRP has an mRNA protection function in addition to a protein targeting function, thus controlling mRNA and protein expression. In this study, we tested involvement of these factors in αSyn biogenesis. We hypothesize that loss of these factors may interfere with αSyn expression, and subsequently, be associated with PD. Using depletion assays in human cell culture and analysis of these proteins in the brains of deceased PD patients, we demonstrate that SRP and AGO2 are involved in the control of αSyn expression and AGO2 has reduced expression in PD. We show for the first time that SRP is involved in mRNA protection of αSyn, a protein that does not have a signal sequence or transmembrane span. Our findings suggest that SRP may interact with a hydrophobic domain in the middle of αSyn during translation. Understanding the molecular mechanisms controlling αSyn biogenesis in cells is vital to developing preventative therapies against PD.


Asunto(s)
Enfermedad de Parkinson/metabolismo , Partícula de Reconocimiento de Señal/metabolismo , alfa-Sinucleína/biosíntesis , Proteínas Argonauta/genética , Proteínas Argonauta/metabolismo , Células HeLa , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Sustancia Negra/metabolismo , Sustancia Negra/patología , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismo
9.
Cells ; 10(9)2021 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-34571878

RESUMEN

Parkinson's disease (PD) is the most prevalent movement disorder characterized with loss of dopaminergic neurons in the brain. One of the pathological hallmarks of the disease is accumulation of aggregated α-synuclein (αSyn) in cytoplasmic Lewy body inclusions that indicates significant dysfunction of protein homeostasis in PD. Accumulation is accompanied with highly elevated S129 phosphorylation, suggesting that this posttranslational modification is linked to pathogenicity and altered αSyn inclusion dynamics. To address the role of S129 phosphorylation on protein dynamics further we investigated the wild type and S129A variants using yeast and a tandem fluorescent timer protein reporter approach to monitor protein turnover and stability. Overexpression of both variants leads to inhibited yeast growth. Soluble S129A is more stable and additional Y133F substitution permits αSyn degradation in a phosphorylation-independent manner. Quantitative cellular proteomics revealed significant αSyn-dependent disturbances of the cellular protein homeostasis, which are increased upon S129 phosphorylation. Disturbances are characterized by decreased abundance of the ubiquitin-dependent protein degradation machinery. Biotin proximity labelling revealed that αSyn interacts with the Rpt2 base subunit. Proteasome subunit depletion by reducing the expression of the corresponding genes enhances αSyn toxicity. Our studies demonstrate that turnover of αSyn and depletion of the proteasome pool correlate in a complex relationship between altered proteasome composition and increased αSyn toxicity.


Asunto(s)
Complejo de la Endopetidasa Proteasomal/metabolismo , Saccharomyces cerevisiae/metabolismo , Ubiquitina/metabolismo , alfa-Sinucleína/metabolismo , Cromatografía Líquida de Alta Presión , Regulación hacia Abajo , Genotipo , Humanos , Espectrometría de Masas , Mutagénesis Sitio-Dirigida , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Fosforilación , Complejo de la Endopetidasa Proteasomal/genética , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Proteoma/análisis , Saccharomyces cerevisiae/genética , alfa-Sinucleína/genética
10.
J Agric Food Chem ; 69(40): 12030-12038, 2021 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-34586801

RESUMEN

The contamination of mycotoxin zearalenone (ZEN) in foods has been reported worldwide, resulting in potential risks to food safety. However, the toxic mechanism of ZEN on neurodegenerative diseases has not been fully elucidated. Therefore, this study conducted in vivo ZEN neurotoxicity assessment on Parkinson's disease (PD)-related dopaminergic neurodegeneration and mitochondrial dysfunction using Caenorhabditis elegans. The results demonstrated that dopaminergic neuron damage was induced by ZEN exposure (1.25, 10, and 50 µM), and dopaminergic neuron-related behaviors were adversely affected subsequently. Additionally, the mitochondrial fragmentation was significantly increased by ZEN exposure. Moreover, upregulated expression of mitochondrial fission and cell apoptosis-related genes (drp-1, egl-1, ced-4, and ced-3) revealed the crucial role of DRP-1 on ZEN-induced neurotoxicity, which was further confirmed by drp-1 mutant and RNAi assays. In conclusion, our study indicates ZEN-induced dopaminergic neurodegeneration via DRP-1-involved mitochondrial fragmentation and apoptosis, which might cause harmful effects on PD-related symptoms.


Asunto(s)
Proteínas de Caenorhabditis elegans , Enfermedad de Parkinson , Zearalenona , Animales , Apoptosis , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Neuronas Dopaminérgicas , Mitocondrias/genética , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Zearalenona/metabolismo , Zearalenona/toxicidad
11.
Sci Rep ; 11(1): 18550, 2021 09 20.
Artículo en Inglés | MEDLINE | ID: mdl-34545158

RESUMEN

Parkinson's disease (PD) is a progressive neurodegenerative disease presenting with motor and non-motor symptoms, including skin disorders (seborrheic dermatitis, bullous pemphigoid, and rosacea), skin pathological changes (decreased nerve endings and alpha-synuclein deposition), and metabolic changes of sebum. Recently, a transcriptome method using RNA in skin surface lipids (SSL-RNAs) which can be obtained non-invasively with an oil-blotting film was reported as a novel analytic method of sebum. Here we report transcriptome analyses using SSL-RNAs and the potential of these expression profiles with machine learning as diagnostic biomarkers for PD in double cohorts (PD [n = 15, 50], controls [n = 15, 50]). Differential expression analysis between the patients with PD and healthy controls identified more than 100 differentially expressed genes in the two cohorts. In each cohort, several genes related to oxidative phosphorylation were upregulated, and gene ontology analysis using differentially expressed genes revealed functional processes associated with PD. Furthermore, machine learning using the expression information obtained from the SSL-RNAs was able to efficiently discriminate patients with PD from healthy controls, with an area under the receiver operating characteristic curve of 0.806. This non-invasive gene expression profile of SSL-RNAs may contribute to early PD diagnosis based on the neurodegeneration background.


Asunto(s)
Aprendizaje Automático , Enfermedad de Parkinson/diagnóstico , Sebo/metabolismo , Transcriptoma , Anciano , Biomarcadores , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Fosforilación
12.
Molecules ; 26(17)2021 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-34500807

RESUMEN

A novel class of styryl sulfones were designed and synthesized as CAPE derivatives by our work team, which showed a multi-target neuroprotective effect, including antioxidative and anti-neuroinflammatory properties. However, the underlying mechanisms remain unclear. In the present study, the anti-Parkinson's disease (PD) activity of 10 novel styryl sulfone compounds was screened by the cell viability test and the NO inhibition test in vitro. It was found that 4d exhibited the highest activity against PD among them. In a MPTP-induced mouse model of PD, the biological activity of 4d was validated through suppressing dopamine neurotoxicity, microglial activation, and astrocytes activation. With compound 4d, we conducted the mechanistic studies about anti-inflammatory responses through inhibition of p38 phosphorylation to protect dopaminergic neurons, and antioxidant effects through promoting nuclear factor erythroid 2-related factor 2 (Nrf2). The results revealed that 4d could significantly inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+)-induced p38 mitogen-activated protein kinase (MAPK) activation in both in vitro and in vivo PD models, thus inhibiting the NF-κB-mediated neuroinflammation-related apoptosis pathway. Simultaneously, it could promote Nrf2 nuclear transfer, and upregulate the expression of antioxidant phase II detoxification enzymes HO-1 and GCLC, and then reduce oxidative damage.


Asunto(s)
Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Estirenos/farmacología , Sulfonas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Células Cultivadas , Inflamación/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Estrés Oxidativo/efectos de los fármacos , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Estirenos/síntesis química , Estirenos/química , Sulfonas/síntesis química , Sulfonas/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo
13.
Int J Mol Sci ; 22(18)2021 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-34576000

RESUMEN

BACKGROUND: Parkinson's disease (PD) is currently the second most common neurodegenerative disorder, burdening about 10 million elderly individuals worldwide. The multifactorial nature of PD poses a difficult obstacle for understanding the mechanisms involved in its onset and progression. Currently, diagnosis depends on the appearance of clinical signs, some of which are shared among various neurologic disorders, hindering early diagnosis. There are no effective tools to prevent PD onset, detect the disease in early stages or accurately report the risk of disease progression. Hence, there is an increasing demand for biomarkers that may identify disease onset and progression, as treatment-based medicine may not be the best approach for PD. Over the last few decades, the search for molecular markers to predict susceptibility, aid in accurate diagnosis and evaluate the progress of PD have intensified, but strategies aimed to improve individualized patient care have not yet been established. CONCLUSIONS: Genomic variation, regulation by epigenomic mechanisms, as well as the influence of the host gut microbiome seem to have a crucial role in the onset and progress of PD, thus are considered potential biomarkers. As such, the human nuclear and mitochondrial genome, epigenome, and the host gut microbiome might be the key elements to the rise of personalized medicine for PD patients.


Asunto(s)
Epigenoma , Microbioma Gastrointestinal , Genoma Humano , Genoma Mitocondrial , Enfermedad de Parkinson , Biomarcadores/metabolismo , Variación Genética , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/microbiología
14.
Int J Mol Sci ; 22(18)2021 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-34576325

RESUMEN

One of the utmost frequently emerging neurodegenerative diseases, Parkinson's disease (PD) must be comprehended through the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD.


Asunto(s)
Enfermedad de Parkinson/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Animales , Humanos , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Estrés Oxidativo/genética , Estrés Oxidativo/fisiología , Enfermedad de Parkinson/genética , Receptores Activados del Proliferador del Peroxisoma/genética
15.
Int J Mol Sci ; 22(17)2021 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-34502283

RESUMEN

Parkinson's disease (PD) is characterized by a loss of dopaminergic cells in the substantia nigra, and its histopathological features include the presence of fibrillar aggregates of α-synuclein (α-syn), which are called Lewy bodies and Lewy neurites. Lewy pathology has been identified not only in the brain but also in various tissues, including muscles. This study aimed to investigate the link between serine/arginine-rich protein specific kinase 3 (srpk3) and α-syn in muscles in PD. We conducted experiments on the quadriceps femoris of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and the C2C12 cell line after treatment with 1-methyl-4-phenylpyridinium (MPP+) and srpk3 short interfering RNA (siRNA). Compared to the control group, the MPTP group showed significantly reduced expression of srpk3, but increased expression of α-syn. In MPP+-treated C2C12 cells, srpk3 expression gradually decreased and α-syn expression increased with the increasing MPP+ concentration. Moreover, experiments in C2C12 cells using srpk3 siRNA showed increased expressions of α-syn and phosphorylated α-syn. Our results showed that srpk3 expression could be altered by MPTP intoxication in muscles, and this change may be related to changes in α-syn expression. Furthermore, this study could contribute to advancement of research on the mechanism by which srpk3 plays a role in PD.


Asunto(s)
Músculo Esquelético/metabolismo , Enfermedad de Parkinson/etiología , Proteínas Serina-Treonina Quinasas/metabolismo , alfa-Sinucleína/metabolismo , 1-Metil-4-fenilpiridinio/toxicidad , Animales , Línea Celular , Modelos Animales de Enfermedad , Intoxicación por MPTP/etiología , Masculino , Ratones Endogámicos C57BL , Músculo Esquelético/fisiopatología , Enfermedad de Parkinson/metabolismo , Proteínas Serina-Treonina Quinasas/genética
16.
Neurol Sci ; 42(11): 4459-4469, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34480241

RESUMEN

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disorder that affects 1% of the population worldwide. Etiology of PD is likely to be multi-factorial such as protein misfolding, mitochondrial dysfunction, oxidative stress, and neuroinflammation that contributes to the pathology of Parkinson's disease (PD), numerous studies have shown that mitochondrial dysfunction may play a key role in the dopaminergic neuronal loss. In multiple ways, the two most important are the activation of neuroinflammation and mitochondrial dysfunction, while mitochondrial dysfunction could cause neuroinflammation and vice versa. Thus, the mitochondrial proteins are the highly promising target for the development of PD. However, the limited amount of dopaminergic neurons prevented the detailed investigation of Parkinson's disease with regard to mitochondrial dysfunction. Both genetic and environmental factors are also associated with mitochondrial dysfunction and PD pathogenesis. The induction of PD by neurotoxins that inhibit mitochondrial complex I provide direct evidence linking mitochondrial dysfunction to PD. A decrease of mitochondrial complex I activity is observed in PD brain and in neurotoxin- or genetic factor-induced in vitro and in vivo models. Moreover, PINK1, Parkin, DJ-1 and LRRK2 mitochondrial PD gene products have important roles in mitophagy, a cellular process that clear damaged mitochondria. This review paper would discuss the evidence for the mitochondrial dysfunction and neuroinflammation in PD.


Asunto(s)
Enfermedad de Parkinson , Neuronas Dopaminérgicas , Humanos , Mitocondrias/metabolismo , Proteínas Mitocondriales , Estrés Oxidativo , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo
17.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-34502404

RESUMEN

Rodent models of Parkinson's disease are based on transgenic expression of mutant synuclein, deletion of PD genes, injections of MPTP or rotenone, or seeding of synuclein fibrils. The models show histopathologic features of PD such as Lewi bodies but mostly only subtle in vivo manifestations or systemic toxicity. The models only partly mimic a predominant loss of dopaminergic neurons in the substantia nigra. We therefore generated mice that express the transgenic diphtheria toxin receptor (DTR) specifically in DA neurons by crossing DAT-Cre mice with Rosa26 loxP-STOP-loxP DTR mice. After defining a well-tolerated DTx dose, DAT-DTR and DTR-flfl controls were subjected to non-toxic DTx treatment (5 × 100 pg/g) and subsequent histology and behavioral tests. DAT protein levels were reduced in the midbrain, and tyrosine hydroxylase-positive neurons were reduced in the substantia nigra, whereas the pan-neuronal marker NeuN was not affected. Despite the promising histologic results, there was no difference in motor function tests or open field behavior. These are tests in which double mutant Pink1-/-SNCAA53T Parkinson mice show behavioral abnormalities. Higher doses of DTx were toxic in both groups. The data suggest that DTx treatment in mice with Cre/loxP-driven DAT-DTR expression leads to partial ablation of DA-neurons but without PD-reminiscent behavioral correlates.


Asunto(s)
Factor de Crecimiento Similar a EGF de Unión a Heparina/genética , Enfermedad de Parkinson/fisiopatología , Animales , Encéfalo/patología , Cuerpo Estriado/metabolismo , Toxina Diftérica/metabolismo , Toxina Diftérica/farmacología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/patología , Femenino , Factor de Crecimiento Similar a EGF de Unión a Heparina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Enfermedad de Parkinson/metabolismo , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Sustancia Negra/patología , Tirosina 3-Monooxigenasa/metabolismo , alfa-Sinucleína/metabolismo
18.
Cells ; 10(9)2021 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-34571901

RESUMEN

A critical aspect of real-time PCR is the presence of housekeeping genes (HKGs) as an internal control for the normalization of expression data for genes of interest. It is necessary to select correct HKGs in the investigation of various pathologies. Thereby, we analyzed the stability of expression of the HKGs in Parkinson's disease (PD). The work was carried out in the peripheral blood of patients with PD and in the brain tissues and peripheral blood of mice with MPTP-induced PD. As a result, Aars was the most stably expressed HKG in the mouse brain as a whole. However, different genes were more stably expressed in different parts of the brain. Polr2f was the most stably expressed in the cortex, Psmd6 was the most stably expressed in the cerebellum, and Psmd7 was the most stably expressed in the striatum and substantia nigra. HKGs were different in similar tissues of the studied organisms. Polr2f was the most stably expressed HKG in the peripheral blood of mice, whereas PSMD6 was the most stably expressed gene in humans. Thus, there is no universal HKG both for different brain tissues of one organism and for similar tissues of different organisms. Furthermore, the identified most stably expressed HKGs can be considered as such only under conditions in PD.


Asunto(s)
Regulación de la Expresión Génica , Genes Esenciales , Enfermedad de Parkinson/patología , ARN Mensajero/metabolismo , Anciano , Animales , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , ARN Mensajero/genética , Estándares de Referencia
19.
Cells ; 10(9)2021 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-34572052

RESUMEN

Accumulation of α-synuclein (α-syn) into Lewy bodies (LBs) and mitochondrial abnormalities are the two cardinal pathobiological features of Parkinson's disease (PD), which are associated with the loss of dopaminergic neurons. Although α-syn accumulates in many different cellular and mouse models, these models generally lack LB features. Here, we generated midbrain dopaminergic (mDA) neuronal cultures from induced pluripotent stem cells (iPSCs) derived from familial PD (fPD) patients and healthy controls. We show that mDA neuronal cultures from fPD patients with A53T mutation and α-syn gene (SNCA) triplication display pathological α-syn deposits, which spatially and morphologically resemble LBs. Importantly, we did not find any apparent accumulation of pathological α-syn in mDA neuronal culture derived from a healthy donor. Furthermore, we show that there are morphological abnormalities in the mitochondrial network in mDA neuronal cultures from fPD patients. Consequently, these cells were more susceptible to mitochondrial damage compared with healthy donor-derived mDA neuronal cultures. Our results indicate that the iPSC-derived mDA neuronal culture platform can be used to investigate the spatiotemporal appearance of LBs, as well as their composition, architecture, and relationship with mitochondrial abnormalities.


Asunto(s)
Diferenciación Celular , Neuronas Dopaminérgicas/patología , Células Madre Pluripotentes Inducidas/patología , Mitocondrias/patología , Enfermedad de Parkinson/patología , Sinucleinopatías/patología , alfa-Sinucleína/metabolismo , Adulto , Estudios de Casos y Controles , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Femenino , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Mutación , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Sinucleinopatías/etiología , Sinucleinopatías/metabolismo , Adulto Joven , alfa-Sinucleína/genética
20.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-34576228

RESUMEN

Human Angiogenin (hANG, or ANG, 14.1 kDa) promotes vessel formation and is also called RNase 5 because it is included in the pancreatic-type ribonuclease (pt-RNase) super-family. Although low, its ribonucleolytic activity is crucial for angiogenesis in tumor tissues but also in the physiological development of the Central Nervous System (CNS) neuronal progenitors. Nevertheless, some ANG variants are involved in both neurodegenerative Parkinson disease (PD) and Amyotrophic Lateral Sclerosis (ALS). Notably, some pt-RNases acquire new biological functions upon oligomerization. Considering neurodegenerative diseases correlation with massive protein aggregation, we analyzed the aggregation propensity of ANG and of three of its pathogenic variants, namely H13A, S28N, and R121C. We found no massive aggregation, but wt-ANG, as well as S28N and R121C variants, can form an enzymatically active dimer, which is called ANG-D. By contrast, the enzymatically inactive H13A-ANG does not dimerize. Corroborated by a specific cross-linking analysis and by the behavior of H13A-ANG that in turn lacks one of the two His active site residues necessary for pt-RNases to self-associate through the three-dimensional domain swapping (3D-DS), we demonstrate that ANG actually dimerizes through 3D-DS. Then, we deduce by size exclusion chromatography (SEC) and modeling that ANG-D forms through the swapping of ANG N-termini. In light of these novelties, we can expect future investigations to unveil other ANG determinants possibly related with the onset and/or development of neurodegenerative pathologies.


Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Enfermedad de Parkinson/genética , Ribonucleasa Pancreática/química , Esclerosis Amiotrófica Lateral/metabolismo , Cromatografía , Cristalografía por Rayos X , Dimerización , Variación Genética , Humanos , Modelos Moleculares , Mutación , Enfermedad de Parkinson/metabolismo , Fosforilación , Conformación Proteica , Dominios Proteicos , Ribonucleasa Pancreática/metabolismo , Ribonucleasas/metabolismo , Sulfonas/química
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