Modulation of dopamine transporter function by α‐synuclein is altered by impairment of cell adhesion and by induction of oxidative stress

  title={Modulation of dopamine transporter function by $\alpha$‐synuclein is altered by impairment of cell adhesion and by induction of oxidative stress},
  author={Christophe Wersinger and Delphine Prou and Philippe Vernier and Anita Sidhu},
  journal={The FASEB Journal},
Human α‐synuclein accumulates in dopaminergic neurons as intraneuronal inclusions, Lewy bodies, which are characteristic of idiopathic Parkinson's disease (PD). Here, we suggest that modulation of the functional activity of the dopamine transporter (DAT) by α‐synuclein may be a key factor in the preferential degeneration of mesencephalic dopamine (DA)‐synthesizing neurons in PD. In cotransfected Ltk‐, HEK 293, and SK‐N‐MC cells, α‐synuclein induced a 35% decrease in [3H]DA uptake. Biotinylated… 

RNA interference‐mediated knockdown of α‐synuclein protects human dopaminergic neuroblastoma cells from MPP+ toxicity and reduces dopamine transport

The results show that RNAi‐mediated α‐synuclein knockdown alters cellular dopamine homeostasis in human cells and may suggest a mechanism for the increased survival in the presence of MPP+, a toxin used extensively to model Parkinson's disease.

Modulation of the trafficking of the human serotonin transporter by human alpha‐synuclein

A novel physiological role for α‐Syn is suggested in regulating SERT activity and may be of relevance in certain mental illnesses and in depression, in which SERT function is believed to be dysregulated.

α-Synuclein Stimulates a Dopamine Transporter-dependent Chloride Current and Modulates the Activity of the Transporter*

Findings are consistent with the interpretation that DAT/α-synuclein interaction at the cell surface results in a DAT-dependent, Na+-insensitive, Cl-sensitive inward current with a decrease in substrate uptake, suggesting that Dat/ α-syn nuclein interaction can modulate dopamine transmission and thus neuronal function.

Parkin Disrupts the α-Synuclein/Dopamine Transporter Interaction: Consequences Toward Dopamine-induced Toxicity

It is reported that parkin, an E2-dependent E3 protein ubiquitin ligase associated with recessive early onset Parkinson’s disease, exerts a protective effect against DA-induced α-synuclein-dependent cell toxicity.

Alpha‐synuclein aggregation and cell death triggered by energy deprivation and dopamine overload are counteracted by D2/D3 receptor activation

It was found that GD induced the formation of fibrillary aggregated α‐syn inclusions containing the DA transporter in dopaminergic cells, which indicate that glucose starvation is likely involved in the induction of PD‐related pathological changes in dopaminationergic neurons.

Could a loss of α‐synuclein function put dopaminergic neurons at risk?

This review focuses on how a loss of normal α‐synuclein function may contribute to the dopamine‐related loss of substantia nigra neurons during Parkinson's disease pathogenesis.

The effect of α‐synuclein knockdown on MPP+ toxicity in models of human neurons

Overall, these results show that as well as having a number of effects on cellular events upstream of mitochondrial dysfunction α‐synuclein affects pathways downstream of superoxide production, possibly involving regulation of NOS activity.

Attenuation of the norepinephrine transporter activity and trafficking via interactions with α‐synuclein

It is proposed that a primary physiological role of α‐Syn may be to regulate the homeostasis of monoamines in synapses, through modulatory interactions of the protein with monoaminergic transporters.

Regulation of the norepinephrine transporter by α‐synuclein‐mediated interactions with microtubules

The findings suggest that the surface localization and activity of NET is modulated by α‐Syn in a manner that is both dependent on interactions with the MT cytoskeleton and varies across brain regions.



Direct binding and functional coupling of α-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis.

It is reported that α-synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non-Aβ amyloid component of α- synuclein to the carboxyl-terminal tail of the hDAT accelerate dopamine-induced apoptosis.

Attenuation of dopamine transporter activity by α-synuclein

Effect of Mutant α-Synuclein on Dopamine Homeostasis in a New Human Mesencephalic Cell Line*

Results suggest that mutant α-synuclein leads to an impairment in vesicular dopamine storage and consequent accumulation of dopamine in the cytosol, a pathogenic mechanism that underlies the toxicity of the psychostimulant amphetamine and the parkinsonian neurotoxin 1-methyl-4-phenylpyridinium.

Physiology and Pathophysiology of α‐Synuclein: Cell Culture and Transgenic Animal Models Based on a Parkinson's Disease‐associated Protein

Abstract: The 15–20 kDa synuclein (SYN) phosphoproteins are abundantly expressed in nervous tissue. Members of the family include α‐ and β‐SYN, and the more distantly related γ‐SYN and synoretin. SYN

α‐Synuclein and Parkinson's disease

Findings to date suggest that α‐syn‐based models represent a paradigm, which is closest to the human pathology, which has hindered the development of models to study Parkinson's disease.

Increased Expression of Rat Synuclein in the Substantia Nigra Pars Compacta Identified by mRNA Differential Display in a Model of Developmental Target Injury

It is concluded that up‐regulation of synuclein in the target injury model is unlikely to mediate apoptotic death and proposed that it may be due to a compensatory response in neurons destined to survive.

Dopamine-dependent neurotoxicity of α-synuclein: A mechanism for selective neurodegeneration in Parkinson disease

It is shown that accumulation of α-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species.

Oxidative post‐translational modifications of α‐synuclein in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinson's disease

It is shown that wild‐type α‐synuclein is a selective target for nitration following peroxynitrite exposure of stably transfected HEK293 cells and is a target for tyrosine nitration, which, by disrupting its biophysical properties, may be relevant to the putative role of α‐ synuclein in the neurodegeneration associated with MPTP toxicity and with PD.

A Role for α-Synuclein in the Regulation of Dopamine Biosynthesis

Data suggest that α-synuclein plays a role in the regulation of dopamine biosynthesis, acting to reduce the activity of tyrosine hydroxylase.

α‐Synuclein regulates neuronal survival via Bcl‐2 family expression and PI3/Akt kinase pathway

  • Ji-Heui SeoJ. Rah Y. Suh
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2002
It is shown that α‐SN plays dual roles of neuroprotection and neurotoxicity depending on its concentration or level of expression, and at nanomolar concentrations, α‐ SN protected neurons against serum deprivation, oxidative stress, and excitotoxicity through the PI3/Akt signaling pathway.