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

Arianna Bellucci, Ginetta Collo, Ilenia Sarnico, Leontino Battistin, Cristina Missale, Pierfranco Spano

Research output: Contribution to journalArticlepeer-review

Abstract

Progressive degeneration and intraneuronal Lewy bodies made of filamentous α-synuclein (α-syn) in dopaminergic cells of the nigrostriatal system are characteristics of Parkinson's disease (PD). Glucose uptake is reduced in some of the brain regions affected by PD neurodegenerative changes. Defects in mitochondrial activity in the substantia nigra have been observed in the brain of patients affected by PD and sub- stantia nigra lesions can induce the onset of a secondary parkinsonism. Thus, energy starvation and consequently metabolic impairment to dopaminergic neurons may be related to the onset of PD. On this line, we evaluated the effect of nutrient starvation, reproduced 'in vitro' by glucose deprivation (GD), in primary mesecephalic neuronal cultures and dopaminergic-differentiated SH-SY5Y cells, to evaluate if decreased glucose support to dopaminergic cells can lead to mitochondrial damage, neurodegeneration and α-syn mis- folding. Furthermore, we investigated the effect of dopamine (DA) treatment in the presence of a DA-uptake inhibitor or of the D2/D3 receptor (D2R/D3R) agonist quinpirole on GD- treated cells, to evaluate the efficacy of these therapeutic compounds. We found that GD induced the formation of fibrillary aggregated α-syn inclusions containing the DA transporter in dopaminergic cells. These alterations were accompanied by dopaminergic cell death and were exacerbated by DA overload. Conversely, the block of DA uptake and D 2R/D3R agonist treatment exerted neuroprotective effects. These data indicate that glucose starvation is likely involved in the induction of PD-related pathological changes in dopaminergic neurons. These changes may be counteracted by the block of DA uptake and by dopaminergic agonist treatment.

Original languageEnglish
Pages (from-to)560-577
Number of pages18
JournalJournal of Neurochemistry
Volume106
Issue number2
DOIs
Publication statusPublished - Jul 2008

Keywords

  • α-synuclein
  • D/D receptor agonists
  • Dopamine overload
  • Dopamine transporter
  • Glucose deprivation
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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