title: Ser129 phosphorylation of endogenous α-synuclein induced by overexpression of polo-like kinases 2 and 3 in nigral dopamine neurons is not detrimental to their survival and function.
abstract: Phosphorylation of the α-synuclein (α-syn) protein at Ser129 [P(S129)-α-syn] was found to be the most abundant form in intracellular inclusions in brains from Parkinson's disease (PD) patients. This finding suggests that P(S129)-α-syn plays a central role in the pathogenesis of PD. However, it is at present unclear whether P(S129)-α-syn is pathogenic driving the neurodegenerative process. Rodent studies using neither the phosphomimics of human α-syn nor co-expression of human wild-type α-syn and kinases phosphorylating α-syn at Ser129 gave consistent results. One major concern in interpreting these findings is that human α-syn was expressed above physiological levels inducing neurodegeneration in rat nigral neurons. In order to exclude this confounding factor, we took a different approach and increased the phosphorylation level of endogenous α-syn. For this purpose, we took advantage of recombinant adeno-associated viral (rAAV) vectors to deliver polo-like kinase (PLK) 2 or PLK3 in the substantia nigra and investigated whether increased levels of P(S129)-α-syn compromised the function and survival of nigral dopaminergic neurons. Interestingly, we observed that hyperphosphorylated α-syn did not induce nigral dopaminergic cell death, as assessed at 1 and 4months. Furthermore, histological analysis did not show any accumulation of α-syn protein or formation of inclusions. Using in vivo microdialysis, we found that the only measurable functional alteration was the depolarisation-induced release of dopamine, while the in vivo synthesis rate of DOPA and dopamine baseline release remained unaltered. Taken together, our results suggest that phosphorylation of α-syn at Ser129 does not confer a toxic gain of function per se.
authors.affiliation: Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, Sweden. Electronic address: kerstin.buck@imail.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Buck
authors.affiliation: Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, Sweden.
authors.forename: Natalie
authors.initials: N
authors.lastname: Landeck
authors.affiliation: Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, Sweden.
authors.forename: Ayse
authors.initials: A
authors.lastname: Ulusoy
authors.affiliation: Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Nour K
authors.initials: NK
authors.lastname: Majbour
authors.affiliation: Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Omar M A
authors.initials: OM
authors.lastname: El-Agnaf
authors.affiliation: Brain Repair and Imaging in Neural Systems, Department of Experimental Medical Science, Lund University, BMC D11, 22184 Lund, Sweden.
authors.forename: Deniz
authors.initials: D
authors.lastname: Kirik
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000821:virology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002470:Cell Survival; D000229:Dependovirus; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors / Q000009:adverse effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism* / Q000821:virology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D051844:alpha-Synuclein; D012694:Serine; C486257:Plk3 protein, rat; D017346:Protein Serine-Threonine Kinases; C530504:Plk2 protein, rat; D004298:Dopamine
keywords: Adeno-associated vector; Parkinson's disease; Phosphorylation; Polo-like kinase; α-Synuclein