A tango for two: Dopamine and α‐synuclein synergy may explain nigrostriatal degeneration in Parkinson's disease

Chen, Vivian; Sáez-Atiénzar, Sara

doi:10.1002/mds.27248

Cited by 5 publications

(3 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Some theorise that as toxic α-syn oligomers are stabilised by dopamine [29], LBs deposit in dopamine-rich areas such as the SNpc and peripheral locations like the retina [30,31], leading to the characteristic dopaminergic cell loss reported in these areas in PD. Thus, the selective vulnerability of dopaminergic neurons in the nigrostriatum may have a direct correlate in the retina in PD [32,33].…”

Section: Introductionmentioning

confidence: 99%

Levodopa Rescues Retinal Function in the Transgenic A53T Alpha-Synuclein Model of Parkinson’s Disease

Tran,

Wong,

Vessey

et al. 2024

Biomedicines

View full text Add to dashboard Cite

Background: Loss of substantia nigra dopaminergic cells and alpha-synuclein (α-syn)-rich intraneuronal deposits within the central nervous system are key hallmarks of Parkinson’s disease (PD). Levodopa (L-DOPA) is the current gold-standard treatment for PD. This study aimed to evaluate in vivo retinal changes in a transgenic PD model of α-syn overexpression and the effect of acute levodopa (L-DOPA) treatment. Methods: Anaesthetised 6-month-old mice expressing human A53T alpha-synuclein (HOM) and wildtype (WT) control littermates were intraperitoneally given 20 mg/kg L-DOPA (50 mg levodopa, 2.5 mg benserazide) or vehicle saline (n = 11–18 per group). In vivo retinal function (dark-adapted full-field ERG) and structure (optical coherence tomography, OCT) were recorded before and after drug treatment for 30 min. Ex vivo immunohistochemistry (IHC) on flat-mounted retina was conducted to assess tyrosine hydroxylase (TH) positive cell counts (n = 7–8 per group). Results: We found that photoreceptor (a-wave) and bipolar cell (b-wave) ERG responses (p < 0.01) in A53T HOM mice treated with L-DOPA grew in amplitude more (47 ± 9%) than WT mice (16 ± 9%) treated with L-DOPA, which was similar to the vehicle group (A53T HOM 25 ± 9%; WT 19 ± 7%). While outer retinal thinning (outer nuclear layer, ONL, and outer plexiform layer, OPL) was confirmed in A53T HOM mice (p < 0.01), L-DOPA did not have an ameliorative effect on retinal layer thickness. These findings were observed in the absence of changes to the number of TH-positive amacrine cells across experiment groups. Acute L-DOPA treatment transiently improves visual dysfunction caused by abnormal alpha-synuclein accumulation. Conclusions: These findings deepen our understanding of dopamine and alpha-synuclein interactions in the retina and provide a high-throughput preclinical framework, primed for translation, through which novel therapeutic compounds can be objectively screened and assessed for fast-tracking PD drug discovery.

show abstract

Section: Introductionmentioning

confidence: 99%

Levodopa Rescues Retinal Function in the Transgenic A53T Alpha-Synuclein Model of Parkinson’s Disease

Tran,

Wong,

Vessey

et al. 2024

Biomedicines

View full text Add to dashboard Cite

show abstract

“…DA has been implicated as an important risk factor for α‐syn modification and aggregation. [ 11–13 ] DA induces oligomerization of α‐syn in vitro [ 13 ] and in vivo, [ 14 ] leading to the selective loss of dopaminergic neurons in PD. This relationship between DA and α‐syn has been dubbed “tango”.…”

Section: Introductionmentioning

confidence: 99%

“…This relationship between DA and α‐syn has been dubbed “tango”. [ 11,15 ] On one hand, genetic mutation and the abnormal PTMs can induce oligomerization of α‐syn, which can impair dopaminergic neurons, in turn impaired neurotransmitter storage arising from mutations in α‐syn could lead to cytoplasmic accumulation of DA. [ 10 ] On the other hand, the increased level of cytoplasmic DA might result in DA oxidation and the generation of reactive oxygen species (ROS) [ 10 ] that could modify the structure of α‐syn, eventually leading to α‐syn aggregation, Lewy body formation, and death of neurons.…”

Section: Introductionmentioning

confidence: 99%

Alpha‐Synuclein Dopaminylation Presented in Plasma of Both Healthy Subjects and Parkinson's Disease Patients

Zhao

Huang

Palanisamy

et al. 2020

Proteomics Clinical Apps

View full text Add to dashboard Cite

Purpose Alpha‐synuclein (α‐syn) dopaminylation can lead to the death of dopaminergic neurons in the brain and is a risk factor of Parkinson's disease (PD). This study aims to examine whether such a posttranslational modification (PTM) is presented in human blood plasma. Experimental Design In vitro reaction simulation between α‐syn and dopamine (DA) is conducted to study the biochemical mechanism. Then α‐syn from human blood plasma samples is detected by using immunoprecipitation‐mass spectrometry (IP‐MS). Lastly the levels of endogenous α‐syn and α‐syn dopaminylation in 88 blood plasma samples from patients with PD, major depressive disorder (MDD), and healthy control (HC) are compared. Results DA modifies α‐syn with the addition of dopamine‐quinone (DAQ) into lysine sites of α‐syn in vitro and the addition of DAQ and 3,4‐dihydroxyphenylacetaldehyde (DOPAL) in plasma samples. The unmodified α‐syn between the PD and HC groups showed similar levels. The levels of two peptides, one with lysine 34 (34K) DAQ modification and the other with lysine 23 (23K) ubiquitination, are significantly higher in PD and MDD compared with HC. Conclusions and Clinical Relevance Thus, α‐syn dopaminylation is measurable and might be used to indicatethe presence and progression of neurological disorders.

show abstract

The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease

Vlag

Havekes

Heckman

2020

Eur J of Neuroscience

View full text Add to dashboard Cite

Parkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α‐synuclein accumulation has long been established to play a causal role in the disease, it alone cannot explain the selective degenerative pattern. Recent evidence shows that the selective vulnerability could arise due to the large presence of cytosolic catecholamines and Ca 2+ ions in the substantia nigra pars compacta and LC specifically that can be aberrantly affected by α‐synuclein accumulation. Moreover, each has its own toxic potential, and disturbance of one can exacerbate the toxic effects of the others. This presents a mechanism unique to these areas that can lead to a vicious degenerative cycle. Interestingly, in familial variants of PD, the exact same brain areas are affected, implying the underlying process is likely the same. However, the exact disease mechanisms of many of these genetic variants remain unclear. Here, we review the effects of the PD‐related genes Parkin, PINK1 and DJ‐1. We establish that these mutant varieties can set in motion the same degenerative process involving α‐synuclein, cytosolic catecholamines and Ca 2+ . Additionally, we show indications that model organisms might not accurately represent all components of this central mechanism, explaining why Parkin, PINK1 and DJ‐1 model organisms often lack a convincing PD‐like phenotype.

show abstract

A tango for two: Dopamine and α‐synuclein synergy may explain nigrostriatal degeneration in Parkinson's disease

Cited by 5 publications

References 4 publications

Levodopa Rescues Retinal Function in the Transgenic A53T Alpha-Synuclein Model of Parkinson’s Disease

Levodopa Rescues Retinal Function in the Transgenic A53T Alpha-Synuclein Model of Parkinson’s Disease

Alpha‐Synuclein Dopaminylation Presented in Plasma of Both Healthy Subjects and Parkinson's Disease Patients

The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease

Contact Info

Product

Resources

About