The usual suspects, dopamine and alpha‐synuclein, conspire to cause neurodegeneration

Abstract

Parkinson's disease (PD) is primarily a movement disorder driven by the loss of dopamine‐producing neurons in the substantia nigra (SN). Early identification of the oxidative properties of dopamine implicated it as a potential source of oxidative stress in PD, yet few studies have investigated dopamine neurotoxicity in vivo. The discovery of PD‐causing mutations in α‐synuclein and the presence of aggregated α‐synuclein in the hallmark Lewy body pathology of PD revealed another important player. Despite extensive efforts, the precise role of α‐synuclein aggregation in neurodegeneration remains unclear. We recently manipulated both dopamine levels and α‐synuclein expression in aged mice and found that only the combination of these 2 factors caused progressive neurodegeneration of the SN and an associated motor deficit. Dopamine modified α‐synuclein aggregation in the SN, resulting in greater abundance of α‐synuclein oligomers and unique dopamine‐induced oligomeric conformations. Furthermore, disruption of the dopamine‐α‐synuclein interaction rescued dopaminergic neurons from degeneration in transgenic Caenorhabditis elegans models. In this Perspective, we discuss these findings in the context of known α‐synuclein and dopamine biology, review the evidence for α‐synuclein oligomer toxicity and potential mechanisms, and discuss therapeutic implications. © 2019 International Parkinson and Movement Disorder Society

Neuromelanin, aging, and neuronal vulnerability in Parkinson's disease

“…Further arguing against a major pathogenic contribution of dopamine‐mediated toxicity in hTyr‐overexpressing rodents, it has been recently reported by 2 independent groups that dopamine‐induced toxicity in rodents, either by chronic l ‐dopa treatment or by enhancing TH activity, is only observed in animals displaying additional PD‐related alterations, such as DJ‐1 deficiency or overexpression of PD‐linked A53T mutant α‐synuclein, but not in regular wild‐type animals (as opposed to the PD phenotype observed in wild‐type rodents overexpressing hTyr). Indeed, although high concentrations of dopamine can be acutely toxic, mostly in vitro , the chronic enhancement of dopamine levels does not cause dopaminergic nerve terminal or cell body loss in vivo , probably because of compensatory protective mechanisms . In addition, dopamine‐induced toxicity has been shown to be dependent on α‐synuclein expression, in contrast to the nonessential role of α‐synuclein for neuromelanin‐linked pathology in hTyr‐overexpressing animals (see later for details).…”

Neuronal vulnerability in Parkinson disease: Should the focus be on axons and synaptic terminals?

“…In addition, a DA/α‐syn interaction also seems to play an important detrimental role in early synaptic dysfunction leading to neurodegeneration. High levels of DA cause oligomerization of α‐syn . In addition, mutation of the DA‐interacting site in α‐syn prevents neurotoxicity.…”

“…High levels of DA cause oligomerization of α-syn. 146 In addition, mutation of the DA-interacting site in α-syn prevents neurotoxicity. Thus, future studies to understand the role of oxidized DA, α-syn aggregation, and a high burden on mitochondrial function at the presynaptic terminal will be critical for understanding nigrostriatal DA terminal degeneration.…”

Methamphetamine causes the exhilaration in the brain by dumping dopamine

“…Dopamine which is flown with a neuron into the synapse in the natural communication process, it can be connected to dopamine receptors on beside neurons [34][35][36]. After that, it returns back into the transferring neuron by a specific protein of dopamine transporter.…”