title: Nigrostriatal overabundance of α-synuclein leads to decreased vesicle density and deficits in dopamine release that correlate with reduced motor activity.
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.
authors.affiliation: Neurodegenerative Studies Laboratory, Brain Mind Institute, EPFL, Lausanne, Switzerland.
authors.forename: Meret Nora
authors.initials: MN
authors.lastname: Gaugler
authors.forename: Ozgur
authors.initials: O
authors.lastname: Genc
authors.forename: Wojciech
authors.initials: W
authors.lastname: Bobela
authors.forename: Safa
authors.initials: S
authors.lastname: Mohanna
authors.forename: Mustafa Taleb
authors.initials: MT
authors.lastname: Ardah
authors.forename: Omar Mukhtar
authors.initials: OM
authors.lastname: El-Agnaf
authors.forename: Marco
authors.initials: M
authors.lastname: Cantoni
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Bensadoun
authors.forename: Ralf
authors.initials: R
authors.lastname: Schneggenburger
authors.forename: Graham W
authors.initials: GW
authors.lastname: Knott
authors.forename: Patrick
authors.initials: P
authors.lastname: Aebischer
authors.forename: Bernard Laurent
authors.initials: BL
authors.lastname: Schneider
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000661:Amphetamine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000172:deficiency*; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000648:ultrastructure; D004563:Electrochemistry; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005822:Genetic Vectors / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009154:Mutation / Q000235:genetics; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D013997:Time Factors; D014161:Transduction, Genetic; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
chemical_list: D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D007381:Intermediate Filament Proteins; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; C430456:desmuslin; D015102:3,4-Dihydroxyphenylacetic Acid; D049452:Green Fluorescent Proteins; D000661:Amphetamine; D001058:Apomorphine; D011188:Potassium; D004298:Dopamine; D006719:Homovanillic Acid