Diversity matters – heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease

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.

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Mesenchymal Stem Cells as a Source of Dopaminergic Neurons: A Potential Cell Based Therapy for Parkinson's Disease

Current Stem Cell Research & Therapy ◽

10.2174/1574888x12666161114122059 ◽

2017 ◽

Vol 12 (4) ◽

pp. 326-347 ◽

Cited By ~ 25

Author(s):

Katari Venkatesh ◽

Dwaipayan Sen

Keyword(s):

Parkinson’S Disease ◽

Stem Cells ◽

Parkinson's Disease ◽

Mesenchymal Stem Cells ◽

Dopaminergic Neurons ◽

Cell Based Therapy

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Colchicine Protects Dopaminergic Neurons in a Rat Model of Parkinson's Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527311201070836 ◽

2012 ◽

Vol 11 (7) ◽

pp. 836-843 ◽

Cited By ~ 7

Author(s):

Mohamed Salama ◽

Amr Ellaithy ◽

Basem Helmy ◽

Mohamed El-Gamal ◽

Dina Tantawy ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Rat Model ◽

Dopaminergic Neurons

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Phenotypic manifestation of α-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

Nature Communications ◽

10.1038/s41467-021-23682-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Benedict Tanudjojo ◽

Samiha S. Shaikh ◽

Alexis Fenyi ◽

Luc Bousset ◽

Devika Agarwal ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Multiple System Atrophy ◽

Neuronal Death ◽

Dopaminergic Neurons ◽

De Novo ◽

Dependent Manner ◽

Human Neurons ◽

Phenotypic Manifestation ◽

Induced Aggregation

Abstractα-Synuclein is critical in the pathogenesis of Parkinson’s disease and related disorders, yet it remains unclear how its aggregation causes degeneration of human dopaminergic neurons. In this study, we induced α-synuclein aggregation in human iPSC-derived dopaminergic neurons using fibrils generated de novo or amplified in the presence of brain homogenates from Parkinson’s disease or multiple system atrophy. Increased α-synuclein monomer levels promote seeded aggregation in a dose and time-dependent manner, which is associated with a further increase in α-synuclein gene expression. Progressive neuronal death is observed with brain-amplified fibrils and reversed by reduction of intraneuronal α-synuclein abundance. We identified 56 proteins differentially interacting with aggregates triggered by brain-amplified fibrils, including evasion of Parkinson’s disease-associated deglycase DJ-1. Knockout of DJ-1 in iPSC-derived dopaminergic neurons enhance fibril-induced aggregation and neuronal death. Taken together, our results show that the toxicity of α-synuclein strains depends on aggregate burden, which is determined by monomer levels and conformation which dictates differential interactomes. Our study demonstrates how Parkinson’s disease-associated genes influence the phenotypic manifestation of strains in human neurons.

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

Journal of Parkinson s Disease ◽

10.3233/jpd-202421 ◽

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.

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Imaging mass cytometry reveals generalised deficiency in OXPHOS complexes in Parkinson’s disease

npj Parkinson s Disease ◽

10.1038/s41531-021-00182-x ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Chun Chen ◽

David McDonald ◽

Alasdair Blain ◽

Ashwin Sachdeva ◽

Laura Bone ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Oxidative Phosphorylation ◽

Mitochondrial Dysfunction ◽

Mitochondrial Disease ◽

Dopaminergic Neurons ◽

Neuronal Response ◽

Proteomic Profiling ◽

Mass Cytometry ◽

And Control

AbstractHere we report the application of a mass spectrometry-based technology, imaging mass cytometry, to perform in-depth proteomic profiling of mitochondrial complexes in single neurons, using metal-conjugated antibodies to label post-mortem human midbrain sections. Mitochondrial dysfunction, particularly deficiency in complex I has previously been associated with the degeneration of dopaminergic neurons in Parkinson’s disease. To further our understanding of the nature of this dysfunction, and to identify Parkinson’s disease specific changes, we validated a panel of antibodies targeting subunits of all five mitochondrial oxidative phosphorylation complexes in dopaminergic neurons from Parkinson’s disease, mitochondrial disease, and control cases. Detailed analysis of the expression profile of these proteins, highlighted heterogeneity between individuals. There is a widespread decrease in expression of all complexes in Parkinson’s neurons, although more severe in mitochondrial disease neurons, however, the combination of affected complexes varies between the two groups. We also provide evidence of a potential neuronal response to mitochondrial dysfunction through a compensatory increase in mitochondrial mass. This study highlights the use of imaging mass cytometry in the assessment and analysis of expression of oxidative phosphorylation proteins, revealing the complexity of deficiencies of these proteins within individual neurons which may contribute to and drive neurodegeneration in Parkinson’s disease.

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α-Synuclein-induced dysregulation of neuronal activity contributes to murine dopamine neuron vulnerability

npj Parkinson s Disease ◽

10.1038/s41531-021-00210-w ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Abeer Dagra ◽

Douglas R. Miller ◽

Min Lin ◽

Adithya Gopinath ◽

Fatemeh Shaerzadeh ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuronal Activity ◽

Dopaminergic Neurons ◽

Prolonged Exposure ◽

D2 Receptor ◽

Neuronal Firing ◽

Dopamine Neurons ◽

Loss Of Function ◽

Therapeutic Implications

AbstractPathophysiological damages and loss of function of dopamine neurons precede their demise and contribute to the early phases of Parkinson’s disease. The presence of aberrant intracellular pathological inclusions of the protein α-synuclein within ventral midbrain dopaminergic neurons is one of the cardinal features of Parkinson’s disease. We employed molecular biology, electrophysiology, and live-cell imaging to investigate how excessive α-synuclein expression alters multiple characteristics of dopaminergic neuronal dynamics and dopamine transmission in cultured dopamine neurons conditionally expressing GCaMP6f. We found that overexpression of α-synuclein in mouse (male and female) dopaminergic neurons altered neuronal firing properties, calcium dynamics, dopamine release, protein expression, and morphology. Moreover, prolonged exposure to the D2 receptor agonist, quinpirole, rescues many of the alterations induced by α-synuclein overexpression. These studies demonstrate that α-synuclein dysregulation of neuronal activity contributes to the vulnerability of dopaminergic neurons and that modulation of D2 receptor activity can ameliorate the pathophysiology. These findings provide mechanistic insights into the insidious changes in dopaminergic neuronal activity and neuronal loss that characterize Parkinson’s disease progression with significant therapeutic implications.

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Chemical and Biological Molecules Involved in Differentiation, Maturation, and Survival of Dopaminergic Neurons in Health and Parkinson’s Disease: Physiological Aspects and Clinical Implications

Biomedicines ◽

10.3390/biomedicines9070754 ◽

2021 ◽

Vol 9 (7) ◽

pp. 754

Author(s):

Giulia Gaggi ◽

Andrea Di Credico ◽

Pascal Izzicupo ◽

Giovanni Iannetti ◽

Angela Di Baldassarre ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Dopaminergic Neurons ◽

Potential Role ◽

High Efficiency ◽

Biological Molecules ◽

Alternative Approach ◽

Non Coding Rnas ◽

Set Up

Parkinson’s disease (PD) is one of the most common neurodegenerative disease characterized by a specific and progressive loss of dopaminergic (DA) neurons and dopamine, causing motor dysfunctions and impaired movements. Unfortunately, available therapies can partially treat the motor symptoms, but they have no effect on non-motor features. In addition, the therapeutic effect reduces gradually, and the prolonged use of drugs leads to a significative increase in the number of adverse events. For these reasons, an alternative approach that allows the replacement or the improved survival of DA neurons is very appealing for the treatment of PD patients and recently the first human clinical trials for DA neurons replacement have been set up. Here, we review the role of chemical and biological molecules that are involved in the development, survival and differentiation of DA neurons. In particular, we review the chemical small molecules used to differentiate different type of stem cells into DA neurons with high efficiency; the role of microRNAs and long non-coding RNAs both in DA neurons development/survival as far as in the pathogenesis of PD; and, finally, we dissect the potential role of exosomes carrying biological molecules as treatment of PD.

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