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

Abstract

The mechanism by which dopaminergic neurons are selectively lost in Parkinson disease (PD) is unknown. Here we show that accumulation of alpha-synuclein in cultured human dopaminergic neurons results in apoptosis that requires endogenous dopamine production and is mediated by reactive oxygen species. In contrast, alpha-synuclein is not toxic in non-dopaminergic human cortical neurons, but rather exhibits neuroprotective activity. Dopamine-dependent neurotoxicity is mediated by 54 83-kD soluble protein complexes that contain alpha-synuclein and 14-3-3 protein, which are elevated selectively in the substantia nigra in PD. Thus, accumulation of soluble alpha-synuclein protein complexes can render endogenous dopamine toxic, suggesting a potential mechanism for the selectivity of neuronal loss in PD.

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…protein complexes [129]. Moreover, direct binding and functional coupling of alphaͲsyn to the dopamine transporter (DAT, responsible for the reͲuptake of this neurotransmitter from the synaptic cleft) was reported to accelerate dopamine uptake, increasing dopamine levels in the cytosol and dopamineͲinduced apoptosis [130].…”

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

“…14‐3‐3s have been linked to neurodegeneration. Several proteins implicated in Parkinson's disease (PD), including alpha‐synuclein ( α syn), leucine‐rich repeat kinase 2 (LRRK2), and parkin, interact with 14‐3‐3s7, 8, 9, 10, 11, and 14‐3‐3s colocalizes with α syn in Lewy bodies, the primary pathological hallmark of PD 12, 13. Expression of several 14‐3‐3 isoforms is reduced in α syn models 14, 15.…”

Transcriptional dysregulation in a transgenic model of Parkinson disease

“…Mutant α-syn or overexpression of wildtype α-syn induces cell death in dopaminergic cell lines and in primary dopaminergic cultures (Oluwatosin-Chigbu et al, 2003;Xu et al, 2002;Zhou et al, 2000;Zhou et al, 2002). Transgenic mice expressing mutant or wildtype α-syn show motor deficits, alterations in dopamine levels, and α-syn-positive inclusions (Hashimoto et al, 2003;Maries et al, 2003).…”