scholarly journals Gastrodia elata Blume prevents dopaminergic neuron degeneration via glial Nrf2 signaling in Lrrk2-G2019S Parkinson's disease models

2021 ◽  
Author(s):  
Yu-En Lin ◽  
Chin-Hsien Lin ◽  
En-Peng Ho ◽  
Yi-Ci Ke ◽  
Stavroula Petridi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mouse ◽  
Dopaminergic Neurons ◽  
Dopaminergic Neuron ◽  
Molecular Mechanisms ◽  
Water Extract ◽  
Missense Mutations ◽  
Gastrodia Elata ◽  
G2019s Mutation

Background: Parkinson's disease (PD) remains an incurable neurodegenerative disease. The most frequent missense mutations in familial PD occur in the highly conserved LRRK2/PARK8 gene. Both fly and mouse models of PD carrying the LRRK2 transgene with a dominant G2019S mutation exhibit locomotion defects and loss of dopaminergic neurons. Gastrodia elata Blume (GE) is an herbal medicine traditionally used to treat neurological diseases and has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear. Methods: We pharmacologically treated the Drosophila G2019S model with water extract of GE (WGE) to evaluate the neuroprotective and locomotion-improving effects. The biochemical analyses and genetic manipulations were further applied to dissect the potential molecular pathways involved in WGE treatment. We also validated the effects and mechanisms of WGE in a G2019S transgenic mouse model. Results: We show that these G2019S mutant flies fed with WGE showed improved locomotion and stable dopaminergic neurons. WGE suppressed the accumulation and hyperactivation of G2019S mutant protein in dopaminergic neurons, and activated the antioxidation and detoxification factor Nrf2 in glia. Activated Nrf2 antagonizes G2019S-induced Mad/Smad signaling in glia. The effects of WGE on the Drosophila G2019S model were recapitulated in a G2019S transgenic mouse. Conclusion: We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2 upregulation, unveiling a potential therapeutic avenue for PD. Keywords: Parkinson's disease, Lrrk2, Gastrodia elata Blume, Drosophila, dopaminergic neuron, Nrf2, BMP/Mad, glia

scholarly journals Glial Nrf2 signaling mediates the neuroprotection exerted by Gastrodia elata Blume in Lrrk2-G2019S Parkinson's disease

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yu-En Lin ◽  
Chin-Hsien Lin ◽  
En-Peng Ho ◽  
Yi-Ci Ke ◽  
Stavroula Petridi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Neuronal Loss ◽  
Missense Mutations ◽  
Gastrodia Elata ◽  
Neuroprotective Effects ◽  
G2019s Mutation ◽  
Lrrk2 G2019s

The most frequent missense mutations in familial Parkinson's disease (PD) occur in the highly conserved LRRK2/PARK8 gene with G2019S mutation. We previously established a fly model of PD carrying the LRRK2-G2019S mutation that exhibited the parkinsonism-like phenotypes. An herbal medicine-Gastrodia elata Blume (GE), has been reported to have neuroprotective effects in toxin-induced PD models. However, the underpinning molecular mechanisms of GE beneficiary to G2019S-induced PD remain unclear. Here, we show that these G2019S flies treated with water extracts of GE (WGE) and its bioactive compounds, gastrodin and 4-HBA, displayed locomotion improvement and dopaminergic neuron protection. WGE suppressed the accumulation and hyperactivation of G2019S proteins in dopaminergic neurons, and activated the antioxidation and detoxification factor Nrf2 mostly in the astrocyte-like and ensheathing glia. Glial activation of Nrf2 antagonizes G2019S-induced Mad/Smad signaling. Moreover, we treated LRRK2-G2019S transgenic mice with WGE and found the locomotion declines, the loss of dopaminergic neurons, and the number of hyperactive microglia were restored. WGE also suppressed the hyperactivation of G2019S proteins and regulated the Smad2/3 pathways in the mice brains. We conclude that WGE prevents locomotion defects and the neuronal loss induced by G2019S mutation via glial Nrf2/Mad signaling, unveiling a potential therapeutic avenue for PD.

scholarly journals Alpha-Synuclein: The Interplay of Pathology, Neuroinflammation, and Environmental Factors in Parkinson’s Disease

2020 ◽  
Vol 20 (2-3) ◽  
pp. 55-64
Author(s):  
Songzhe He ◽  
Shan Zhong ◽  
Gang Liu ◽  
Jun Yang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environmental Factors ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Future Directions ◽  
Main Protein ◽  
Cumulative Evidence

<b><i>Background:</i></b> Parkinson’s disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disease. α-Synuclein (α-syn), which is the main protein component of Lewy bodies, plays an important role in the pathological hallmarks of PD. However, the pathological function of α-syn and the molecular mechanisms responsible for the degeneration of dopaminergic neurons are still elusive. <b><i>Summary:</i></b> Cumulative evidence implicates that abnormal processing of α-syn will be predicted to lead to pathological changes in PD. <b><i>Key Messages:</i></b> In this review, we summarize the structure and physiological function of α-syn, and further discuss the interplay of pathology, neuroinflammation, and environmental factors in PD. Additionally, we suggest future directions for understanding the toxicity of α-syn to neurons, which may ultimately encourage us to better design disease-modifying therapeutic strategies for PD.

scholarly journals The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson’s disease

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Aurelie de Rus Jacquet ◽  
Jenna L Tancredi ◽  
Andrew L Lemire ◽  
Michael C DeSantis ◽  
Wei-Ping Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Extracellular Vesicle ◽  
Biological Properties ◽  
Neuronal Firing ◽  
G2019s Mutation ◽  
Lrrk2 G2019s ◽  
Induced Pluripotent ◽  
Dynamic Relationships

Astrocytes are essential cells of the central nervous system, characterized by dynamic relationships with neurons that range from functional metabolic interactions and regulation of neuronal firing activities, to the release of neurotrophic and neuroprotective factors. In Parkinson’s disease (PD), dopaminergic neurons are progressively lost during the course of the disease, but the effects of PD on astrocytes and astrocyte-to-neuron communication remain largely unknown. This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes generated from patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes and identify the abnormal accumulation of key PD-related proteins within multivesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs and that LRRK2 G2019S EVs are abnormally enriched in neurites and fail to provide full neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properties may participate in the progression of PD.

Neuroinflammation caused by activated microglia and astrocytes can contribute to the progression of pathogenic damage to substantia nigra neurons, playing a role in Parkinson's disease progression

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Mitochondrial Dysfunction ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
High Energy ◽  
Molecular Pathways ◽  
Activated Microglia

Parkinson's disease progresses by a number of regionally specific cellular and molecular mechanisms. Furthermore, these pathways interact and have an influence on one another in both normal and pathological conditions. Neuroinflammation caused by activated microglia and astrocytes can contribute to the progression of pathogenic damage to substantia nigra (SN) neurons. Similarly, oxidative stress may be caused by a variety of stressors, such as contaminants in the environment or age-related mitochondrial dysfunction, leading to the production of reactive oxygen species (ROS). Dopamine auto-oxidation is a significant generator of ROS in dopaminergic neurons, resulting in neuronal oxidative stress. The high energy demands of dopaminergic neurons may result in mitochondrial dysfunction and oxidative damage as they age. Because mitophagy clears dysfunctional mitochondria from SN neurons, mutation-related abnormalities in autophagy of defective proteins might allow damaging proteins to accumulate in the cell. Because the effects of aging on these molecular pathways and cellular activities are unknown, further study into these molecular pathways and their connections in normal and sick states will be essential for developing disease-specific therapies.

scholarly journals Dopamine Oxidation and Autophagy

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
Patricia Muñoz ◽  
Sandro Huenchuguala ◽  
Irmgard Paris ◽  
Juan Segura-Aguilar
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Protein Degradation ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
Neurodegenerative Process ◽  
Dopamine Oxidation

The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction,α-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxicα-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i) the formation ofα-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii) the formation of adducts withα- andβ-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.

scholarly journals Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism

2016 ◽  
Vol 113 (15) ◽  
pp. E2180-E2188 ◽  
Author(s):  
Paul D. Dodson ◽  
Jakob K. Dreyer ◽  
Katie A. Jennings ◽  
Emilie C. J. Syed ◽  
Richard Wade-Martins ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Dopaminergic Neuron ◽  
Striatal Dopamine ◽  
Cell Type ◽  
Spontaneous Movement ◽  
Midbrain Dopaminergic Neurons ◽  
Spontaneous Movements

Midbrain dopaminergic neurons are essential for appropriate voluntary movement, as epitomized by the cardinal motor impairments arising in Parkinson’s disease. Understanding the basis of such motor control requires understanding how the firing of different types of dopaminergic neuron relates to movement and how this activity is deciphered in target structures such as the striatum. By recording and labeling individual neurons in behaving mice, we show that the representation of brief spontaneous movements in the firing of identified midbrain dopaminergic neurons is cell-type selective. Most dopaminergic neurons in the substantia nigra pars compacta (SNc), but not in ventral tegmental area or substantia nigra pars lateralis, consistently represented the onset of spontaneous movements with a pause in their firing. Computational modeling revealed that the movement-related firing of these dopaminergic neurons can manifest as rapid and robust fluctuations in striatal dopamine concentration and receptor activity. The exact nature of the movement-related signaling in the striatum depended on the type of dopaminergic neuron providing inputs, the striatal region innervated, and the type of dopamine receptor expressed by striatal neurons. Importantly, in aged mice harboring a genetic burden relevant for human Parkinson’s disease, the precise movement-related firing of SNc dopaminergic neurons and the resultant striatal dopamine signaling were lost. These data show that distinct dopaminergic cell types differentially encode spontaneous movement and elucidate how dysregulation of their firing in early Parkinsonism can impair their effector circuits.

scholarly journals The LRRK2 G2019S mutation alters astrocyte-to-neuron communication via extracellular vesicles and induces neuron atrophy in a human iPSC-derived model of Parkinson’s disease

2020 ◽  
Author(s):  
Aurelie de Rus Jacquet ◽  
Jenna L. Tancredi ◽  
Andrew L. Lemire ◽  
Michael C. DeSantis ◽  
Wei-Ping Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Extracellular Vesicle ◽  
Biological Properties ◽  
Neuronal Firing ◽  
G2019s Mutation ◽  
Lrrk2 G2019s ◽  
Induced Pluripotent ◽  
Dynamic Relationships

AbstractAstrocytes are essential cells of the central nervous system, characterized by dynamic relationships with neurons that range from functional metabolic interactions and regulation of neuronal firing activities, to the release of neurotrophic and neuroprotective factors. In Parkinson’s disease (PD), dopaminergic neurons are progressively lost during the course of the disease, but the effects of PD on astrocytes and astrocyte-to-neuron communication remains largely unknown. This study focuses on the effects of the PD-related mutation LRRK2 G2019S in astrocytes, generated from patient-derived induced pluripotent stem cells. We report the alteration of extracellular vesicle (EV) biogenesis in astrocytes, and we identify the abnormal accumulation of key PD-related proteins within multi vesicular bodies (MVBs). We found that dopaminergic neurons internalize astrocyte-secreted EVs but LRRK2 G2019S EVs are abnormally enriched in neurites and provide only marginal neurotrophic support to dopaminergic neurons. Thus, dysfunctional astrocyte-to-neuron communication via altered EV biological properties may participate in the progression of PD.

Protective Effects of Water Extract of Propolis on Dopaminergic Neurons, Brain Derived Neurotrophic Factor and Stress Oxidative Factors in the Rat Model of Parkinson’s Disease

2015 ◽  
Vol 11 (4) ◽  
pp. 300-308 ◽  
Author(s):  
Manouchehr Safari ◽  
Hamid Reza Sameni ◽  
Leila Badban ◽  
Ahmad Raze Bandegi ◽  
Abbas Ali Vafaei ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Rat Model ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Water Extract ◽  
Brain Derived Neurotrophic Factor ◽  
Protective Effects ◽  
Stress Oxidative
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