Poul Henning Jensen

Ser129D mutant alpha-Synuclein induces earlier Motor Dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's Disease

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Alpha-synuclein phosphorylated at serine 129 (S129) is highly elevated in Parkinson's disease patients where it mainly accumulates in the Lewy bodies. Several groups have studied the role of phosphorylation at the S129 in α-synuclein in a rat model for Parkinson's disease usingrecombinant adeno-associated viral (rAAV) vectors. The results obtained areinconsistent and accordingly the role of S129 phosphorylation in α-synuclein toxicity remains unclear. This prompted us to re-examine the neuropathological and behavioural effects of the S129 modified α-synuclein species in vivo. For this purpose, we used two mutated forms of human α-synuclein in which theS129 was replaced either withan alanine (S129A), to block phosphorylation or with an aspartate (S129D), to mimic phosphorylation, and compared them with the wild typeα-synuclein. This approach was similar in design to the previous studies, however our investigation of dopaminergic degeneration included also performing a detailed study of the α-synuclein induced pathology in the striatum and the analysis of motor deficits. Our results showed that overexpressing S129D or wild type α-synuclein resulted in an accelerated dopaminergic fiber loss as compared with S129A α-synuclein. Furthermore,motor deficit seen in the group treated with the mutant S129Dα-synuclein appeared earlier than the other two forms of α-synuclein. Conversely, S129A α-synucleinshowed significantly larger pathological α-synuclein-positive inclusions, and slower dopaminergic fiber loss, when compared to the other two forms of α-synuclein, suggesting a neuroprotective effect of the mutation.When examined at long-term, all three α-synucleinforms resulted in pathological accumulations of α-synuclein in striatal fibers and dopaminergic cell death in the substantia nigra.Our data show that changes in the S129 residue of α-synucleininfluence the rate of pathology and neurodegeneration, with an overall deleterious effect of exchanging S129 to a residue mimicking its phosphorylated state.
Original languageEnglish
JournalNeurobiology of Disease
Volume56
Pages (from-to)47-58
ISSN0969-9961
DOIs
Publication statusPublished - 13 Aug 2013

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