scholarly journals Dysregulation of the AP2M1 phosphorylation cycle by LRRK2 impairs endocytosis and leads to dopaminergic neurodegeneration

2021 ◽  
Vol 14 (693) ◽  
pp. eabg3555
Author(s):  
Qinfang Liu ◽  
Judith Bautista-Gomez ◽  
Daniel A. Higgins ◽  
Jianzhong Yu ◽  
Yulan Xiong
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Adaptor Protein ◽  
Endocytic Trafficking ◽  
Dopaminergic Neurodegeneration ◽  
Lrrk2 G2019s ◽  
Endocytic Machinery ◽  
Mutant Lrrk2 ◽  
The Brain

Mutations in the kinase LRRK2 and impaired endocytic trafficking are both implicated in the pathogenesis of Parkinson’s disease (PD). Expression of the PD-associated LRRK2 mutant in mouse dopaminergic neurons was shown to disrupt clathrin-mediated endocytic trafficking. Here, we explored the molecular mechanism linking LRRK2 to endocytosis and found that LRRK2 bound to and phosphorylated the μ2 subunit of the adaptor protein AP2 (AP2M1), a core component of the clathrin-mediated endocytic machinery. Analysis of human SH-SY5Y cells and mouse neurons and tissues revealed that loss of LRRK2 abundance or kinase function resulted in decreased phosphorylation of AP2M1, which is required for the initial formation of clathrin-coated vesicles (CCVs). In contrast, overexpression of LRRK2 or expression of a Parkinson’s disease–associated gain-of-function mutant LRRK2 (G2019S) inhibited the uncoating of AP2M1 from CCVs at later stages and prevented new cycles of CCV formation. Thus, the abundance and activity of LRRK2 must be calibrated to ensure proper endocytosis. Dysregulated phosphorylation of AP2M1 from the brain but not thyroid tissues of LRRK2 knockout and G2019S-knockin mice suggests a tissue-specific regulatory mechanism of endocytosis. Furthermore, we found that LRRK2-dependent phosphorylation of AP2M1 mediated dopaminergic neurodegeneration in a Drosophila model of PD. Together, our findings provide a mechanistic link between LRRK2, AP2, and endocytosis in the pathogenesis of PD.

Comparison of Cytocidal Activities of L-DOPA and Dopamine in S. cerevisiae and C. glabrata

2020 ◽  
Vol 16 (1) ◽  
pp. 90-93
Author(s):  
Carmen E. Iriarte ◽  
Ian G. Macreadie
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Candida Glabrata ◽  
High Sensitivity ◽  
Time Dependent ◽  
Colony Forming Units ◽  
Dependent Cell ◽  
The Brain

Background: Parkinson's Disease results from a loss of dopaminergic neurons, and reduced levels of the neurotransmitter dopamine. Parkinson's Disease treatments involve increasing dopamine levels through administration of L-DOPA, which can cross the blood brain barrier and be converted to dopamine in the brain. The toxicity of dopamine has previously studied but there has been little study of L-DOPA toxicity. Methods: We have compared the toxicity of dopamine and L-DOPA in the yeasts, Saccharomyces cerevisiae and Candida glabrata by cell viability assays, measuring colony forming units. Results: L-DOPA and dopamine caused time-dependent cell killing in Candida glabrata while only dopamine caused such effects in Saccharomyces cerevisiae. The toxicity of L-DOPA is much lower than dopamine. Conclusion: Candida glabrata exhibits high sensitivity to L-DOPA and may have advantages for studying the cytotoxicity of L-DOPA.

scholarly journals Multiple Pathways of LRRK2-G2019S/Rab10 Interaction in Dopaminergic Neurons

2021 ◽  
pp. 1-16
Author(s):  
Alison Fellgett ◽  
C. Adam Middleton ◽  
Jack Munns ◽  
Chris Ugbode ◽  
David Jaciuch ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Genetic Interaction ◽  
In Vitro Assays ◽  
Rab Proteins ◽  
Circadian Activity ◽  
Loss Of Function ◽  
Lrrk2 G2019s

Background: Inherited mutations in the LRRK2 protein are the common causes of Parkinson’s disease, but the mechanisms by which increased kinase activity of mutant LRRK2 leads to pathological events remain to be determined. In vitro assays (heterologous cell culture, phospho-protein mass spectrometry) suggest that several Rab proteins might be directly phosphorylated by LRRK2-G2019S. An in vivo screen of Rab expression in dopaminergic neurons in young adult Drosophila demonstrated a strong genetic interaction between LRRK2-G2019S and Rab10. Objective: To determine if Rab10 is necessary for LRRK2-induced pathophysiological responses in the neurons that control movement, vision, circadian activity, and memory. These four systems were chosen because they are modulated by dopaminergic neurons in both humans and flies. Methods: LRRK2-G2019S was expressed in Drosophila dopaminergic neurons and the effects of Rab10 depletion on Proboscis Extension, retinal neurophysiology, circadian activity pattern (‘sleep’), and courtship memory determined in aged flies. Results: Rab10 loss-of-function rescued LRRK2-G2019S induced bradykinesia and retinal signaling deficits. Rab10 knock-down, however, did not rescue the marked sleep phenotype which results from dopaminergic LRRK2-G2019S. Courtship memory is not affected by LRRK2, but is markedly improved by Rab10 depletion. Anatomically, both LRRK2-G2019S and Rab10 are seen in the cytoplasm and at the synaptic endings of dopaminergic neurons. Conclusion: We conclude that, in Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson’s disease.

scholarly journals TFE3-Mediated Autophagy is Involved in Dopaminergic Neurodegeneration in Parkinson’s Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Xin He ◽  
Yue Xie ◽  
Qiongping Zheng ◽  
Zeyu Zhang ◽  
Shanshan Ma ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Death ◽  
Transcription Factor ◽  
Dopaminergic Neurons ◽  
Essential Role ◽  
Dopaminergic Neurodegeneration ◽  
Promising Strategy ◽  
Progressive Loss ◽  
Mptp Model

Impairment of autophagy has been strongly implicated in the progressive loss of nigral dopaminergic neurons in Parkinson’s disease (PD). Transcription factor E3 (TFE3), an MiTF/TFE family transcription factor, has been identified as a master regulator of the genes that are associated with lysosomal biogenesis and autophagy. However, whether TFE3 is involved in parkinsonian neurodegeneration remains to be determined. In this study, we found decreased TFE3 expression in the nuclei of the dopaminergic neurons of postmortem human PD brains. Next, we demonstrated that TFE3 knockdown led to autophagy dysfunction and neurodegeneration of dopaminergic neurons in mice, implying that reduction of nuclear TFE3 may contribute to autophagy dysfunction-mediated cell death in PD. Further, we showed that enhancement of autophagy by TFE3 overexpression dramatically reversed autophagy downregulation and dopaminergic neurons loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Taken together, these findings demonstrate that TFE3 plays an essential role in maintaining autophagy and the survival of dopaminergic neurons, suggesting TFE3 activation may serve as a promising strategy for PD therapy.

Parkinson's Disease

2019 ◽  
pp. 252-273 ◽  
Author(s):  
Vaibhav Walia ◽  
Ashish Gakkhar ◽  
Munish Garg
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Older Patients ◽  
Neurodegenerative Disorder ◽  
Progressive Loss ◽  
The Brain

Parkinson's disease (PD) is a neurodegenerative disorder in which a progressive loss of the dopaminergic neurons occurs. The loss of the neurons is most prominent in the substantia nigra region of the brain. The prevalence of PD is much greater among the older patients suggesting the risk of PD increases with the increase of age. The exact cause of the neurodegeneration in PD is not known. In this chapter, the authors introduce PD, demonstrate its history, pathogenesis, neurobiology, sign and symptoms, diagnosis, and pharmacotherapy.

scholarly journals α-Synuclein pre-formed fibrils induce prion-like protein aggregation and neurotoxicity in C. elegans models of Parkinson's disease

2021 ◽  
Author(s):  
Merry Chen ◽  
Julie Vincent ◽  
Alexis Ezeanii ◽  
Saurabh Wakade ◽  
Shobha Yerigenahally ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Motor Deficit ◽  
Rodent Models ◽  
Neuron Degeneration ◽  
C Elegans ◽  
Dopaminergic Neurodegeneration ◽  
Disease Mechanisms ◽  
The Brain

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the brain in a prion-like manner. While rodent models have recapitulated gut-to-brain α-synuclein transmission, animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first C. elegans models in which feeding with α-synuclein pre-formed fibrils (PFFs) induced prion-like dopamine neuron degeneration and seeding of aggregation of human α-synuclein expressed in the host. PFF acceleration of α-synuclein aggregation in C. elegans muscle cells was associated with a progressive motor deficit, whereas feeding with α-synuclein monomer produced much milder effects. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, and enzymes involved in heparan sulfate proteoglycan biosynthesis, afforded protection from PFF-induced seeding of aggregation and toxicity, as well as dopaminergic neurodegeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.

scholarly journals Association Between Decreased Srpk3 Expression And An Increase In Substantia Nigra Alpha-Synuclein Levels In An MPTP-Induced Parkinson’s Disease Mouse Model

2022 ◽  
Author(s):  
Min Hyung Seo ◽  
Sujung Yeo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Cell Loss ◽  
Alpha Synuclein ◽  
Mice Model ◽  
Dopaminergic Cell ◽  
The Brain

Abstract Parkinson’s disease (PD) is known as the second most common neurodegenerative disease, which is caused by destruction of dopaminergic neurons in the substantia nigra (SN) of the brain; however, the reason for the death of dopaminergic neurons remains unclear. An increase in α-synuclein (α-syn) is considered an important factor in the pathogenesis of PD. In the current study, we investigated the association between PD and serine/arginine-rich protein specific kinase 3 (Srpk3) in MPTP-induced parkinsonism mice model and in SH-SY5Y cells treated with MPP+. Srpk3 expression was significantly downregulated, while tyrosine hydroxylase (TH) decreased and α-synuclein (α-syn) increased after 4 weeks of MPTP intoxication treatment. Dopaminergic cell reduction and α-syn increase were demonstrated by inhibiting Srpk3 expression by siRNA in SH-SY5Y cells. Moreover, a decrease in Srpk3 expression upon siRNA treatment promoted dopaminergic cell reduction and α-syn increase in SH-SY5Y cells treated with MPP+. These results suggest that the decrease in Srpk3 expression due to Srpk3 siRNA caused both a decrease in TH and an increase in α-syn. This raises new possibilities for studying how Srpk3 controls dopaminergic cells and α-syn expression, which may be related to the pathogenesis of PD. Our results provide an avenue for understanding the role of Srpk3 during dopaminergic cell loss and α-syn increase in the SN. Furthermore, this study could support a therapeutic possibility for PD in that the maintenance of Srpk3 expression inhibited dopaminergic cell reduction.

scholarly journals Neuron-Astrocyte Interactions in Parkinson’s Disease

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2623
Author(s):  
Ikuko Miyazaki ◽  
Masato Asanuma
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Therapeutic Strategies ◽  
Pathogenic Role ◽  
Waste Products ◽  
Disease Modifying Drugs ◽  
Dopaminergic Neurodegeneration ◽  
The Central Nervous System

Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

Role of α-synuclein in neurodegeneration: implications for the pathogenesis of Parkinson's disease

2014 ◽  
Vol 56 ◽  
pp. 125-135 ◽  
Author(s):  
Shun Yu ◽  
Piu Chan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Experimental Studies ◽  
Research Progress ◽  
Pathogenic Role ◽  
Normal Expression ◽  
The Brain ◽  
Recent Research Progress

α-Syn (α-synuclein) is a small soluble acidic protein that is extensively expressed in the nervous system. Genetic, clinical and experimental studies demonstrate that α-syn is strongly implicated in the pathogenesis of PD (Parkinson's disease). However, the pathogenic mechanism remains elusive. In the present chapter, we first describe the normal expression and potential physiological functions of α-syn. Then, we introduce recent research progress related to the pathogenic role of α-syn in PD, with special emphasis on how α-syn oligomers cause the preferential degeneration of dopaminergic neurons in the substantia nigra and the spreading of α-syn pathology in the brain of PD patients.

scholarly journals α-Bisabolol, a Dietary Bioactive Phytochemical Attenuates Dopaminergic Neurodegeneration through Modulation of Oxidative Stress, Neuroinflammation and Apoptosis in Rotenone-Induced Rat Model of Parkinson’s Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1421 ◽  
Author(s):  
Hayate Javed ◽  
M. F. Nagoor Meeran ◽  
Sheikh Azimullah ◽  
Lujain Bader Eddin ◽  
Vivek Dhar Dwivedi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Mitochondrial Dysfunction ◽  
Proinflammatory Cytokines ◽  
Rat Model ◽  
Inflammatory Mediators ◽  
Dopaminergic Neurons ◽  
Neuroprotective Effects ◽  
Dopaminergic Neurodegeneration

Rotenone (ROT), a plant-derived pesticide is a well-known environmental neurotoxin associated with causation of Parkinson’s disease (PD). ROT impairs mitochondrial dysfunction being mitochondrial complex-I (MC-1) inhibitor and perturbs antioxidant-oxidant balance that contributes to the onset and development of neuroinflammation and neurodegeneration in PD. Due to the scarcity of agents to prevent the disease or to cure or halt the progression of symptoms of PD, the focus is on exploring agents from naturally occurring dietary phytochemicals. Among numerous phytochemicals, α-Bisabolol (BSB), natural monocyclic sesquiterpene alcohol found in many ornamental flowers and edible plants garnered attention due to its potent pharmacological properties and therapeutic potential. Therefore, the present study investigated the neuroprotective effects of BSB in a rat model of ROT-induced dopaminergic neurodegeneration, a pathogenic feature of PD and underlying mechanism targeting oxidative stress, inflammation and apoptosis. BSB treatment significantly prevented ROT-induced loss of dopaminergic neurons and fibers in the substantia nigra and striatum respectively. BSB treatment also attenuated ROT-induced oxidative stress evidenced by inhibition of MDA formation and GSH depletion as well as improvement in antioxidant enzymes, SOD and catalase. BSB treatment also attenuated ROT-induced activation of the glial cells as well as the induction and release of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) and inflammatory mediators (iNOS and COX-2) in the striatum. In addition to countering oxidative stress and inflammation, BSB also attenuated apoptosis of dopaminergic neurons by attenuating downregulation of anti-apoptotic protein Bcl-2 and upregulation of pro-apoptotic proteins Bax, cleaved caspases-3 and 9. Further, BSB was observed to attenuate mitochondrial dysfunction by inhibiting mitochondrial lipid peroxidation, cytochrome-C release and reinstates the levels/activity of ATP and MC-I. The findings of the study demonstrate that BSB treatment salvaged dopaminergic neurons, attenuated microglia and astrocyte activation, induction of inflammatory mediators, proinflammatory cytokines and reduced the expression of pro-apoptotic markers. The in vitro study on ABTS radical revealed the antioxidant potential of BSB. The results of the present study are clearly suggestive of the neuroprotective effects of BSB through antioxidant, anti-inflammatory and anti-apoptotic properties in ROT-induced model of PD.

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