Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity

Meret Nora Gaugler, Ozgur Genc, Wojciech Bobela, Safa Mohanna, Mustafa Taleb Ardah, Omar Ali El-Agnaf, Marco Cantoni, Jean Charles Bensadoun, Ralf Schneggenburger, Graham W. Knott, Patrick Aebischer, Bernard Laurent Schneider

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

α-Synuclein (α-syn) is a presynaptic protein present at most nerve terminals, but its function remains largely unknown. The familial forms of Parkinson's disease associated with multiplications of the α-syn gene locus indicate that overabundance of this protein might have a detrimental effect on dopaminergic transmission. To investigate this hypothesis, we use adeno-associated viral (AAV) vectors to overexpress human α-syn in the rat substantia nigra. Moderate overexpression of either wild-type (WT) or A30P α-syn differs in the motor phenotypes induced, with only the WT form generating hemiparkinsonian impairments. Wild-type α-syn causes a reduction of dopamine release in the striatum that exceeds the loss of dopaminergic neurons, axonal fibers, and the reduction in total dopamine. At the ultrastructural level, the reduced dopamine release corresponds to a decreased density of dopaminergic vesicles and synaptic contacts in striatal terminals. Interestingly, the membrane-binding-deficient A30P mutant does neither notably reduce dopamine release nor it cause ultrastructural changes in dopaminergic axons, showing that α-syn's membrane-binding properties are critically involved in the presynaptic defects. To further determine if the affinity of the protein for membranes determines the extent of motor defects, we compare three forms of α-syn in conditions leading to pronounced degeneration. While membrane-binding α-syns (wild-type and A53T) induce severe motor impairments, an N-terminal deleted form with attenuated affinity for membranes is inefficient in inducing motor defects. Overall, these results demonstrate that α-syn overabundance is detrimental to dopamine neurotransmission at early stages of the degeneration of nigrostriatal dopaminergic axons.

Original languageEnglish
Pages (from-to)653-669
Number of pages17
JournalActa Neuropathologica
Volume123
Issue number5
DOIs
Publication statusPublished - May 2012
Externally publishedYes

Fingerprint

Synucleins
Dopamine
Motor Activity
Membranes
Axons
Corpus Striatum
Synaptic Vesicles
Dopaminergic Neurons
Substantia Nigra
Synaptic Transmission
Parkinson Disease
Membrane Proteins
Proteins
Phenotype
Genes

Keywords

  • α-Synuclein
  • Dopamine
  • Electron microscopy
  • Motor behavior
  • Neurotransmission
  • Substantia nigra

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity. / Gaugler, Meret Nora; Genc, Ozgur; Bobela, Wojciech; Mohanna, Safa; Ardah, Mustafa Taleb; Ali El-Agnaf, Omar; Cantoni, Marco; Bensadoun, Jean Charles; Schneggenburger, Ralf; Knott, Graham W.; Aebischer, Patrick; Schneider, Bernard Laurent.

In: Acta Neuropathologica, Vol. 123, No. 5, 05.2012, p. 653-669.

Research output: Contribution to journalArticle

Gaugler, MN, Genc, O, Bobela, W, Mohanna, S, Ardah, MT, Ali El-Agnaf, O, Cantoni, M, Bensadoun, JC, Schneggenburger, R, Knott, GW, Aebischer, P & Schneider, BL 2012, 'Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity', Acta Neuropathologica, vol. 123, no. 5, pp. 653-669. https://doi.org/10.1007/s00401-012-0963-y
Gaugler, Meret Nora ; Genc, Ozgur ; Bobela, Wojciech ; Mohanna, Safa ; Ardah, Mustafa Taleb ; Ali El-Agnaf, Omar ; Cantoni, Marco ; Bensadoun, Jean Charles ; Schneggenburger, Ralf ; Knott, Graham W. ; Aebischer, Patrick ; Schneider, Bernard Laurent. / Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity. In: Acta Neuropathologica. 2012 ; Vol. 123, No. 5. pp. 653-669.
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