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

Fabia Febbraro; Gurdal Sahin; Aina Farran; Sofia Soares; Poul H Jensen; Deniz Kirik; Marina Romero-Ramos

doi:10.1016/j.nbd.2013.03.014

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

Fabia Febbraro, Gurdal Sahin, Aina Farran, Sofia Soares, Poul H Jensen, Deniz Kirik, Marina Romero-Ramos

Department of Biomedicine - Forskning og uddannelse, Vest

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Abstract

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 language	English
Journal	Neurobiology of Disease
Volume	56
Pages (from-to)	47-58
ISSN	0969-9961
DOIs	https://doi.org/10.1016/j.nbd.2013.03.014
Publication status	Published - 13 Aug 2013

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@article{cafa0319823d45f4bc5366de45d9e25d,

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

abstract = "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.",

author = "Fabia Febbraro and Gurdal Sahin and Aina Farran and Sofia Soares and Jensen, {Poul H} and Deniz Kirik and Marina Romero-Ramos",

note = "Copyright {\textcopyright} 2013. Published by Elsevier Inc.",

year = "2013",

month = aug,

day = "13",

doi = "10.1016/j.nbd.2013.03.014",

language = "English",

volume = "56",

pages = "47--58",

journal = "Neurobiology of Disease",

issn = "0969-9961",

publisher = "Academic Press",

}

Ser129D mutant alpha-Synuclein induces earlier Motor Dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's Disease. / Febbraro, Fabia; Sahin, Gurdal; Farran, Aina et al.
In: Neurobiology of Disease, Vol. 56, 13.08.2013, p. 47-58.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Ser129D mutant alpha-Synuclein induces earlier Motor Dysfunction while S129A results in distinctive pathology in a rat model of Parkinson's Disease

AU - Febbraro, Fabia

AU - Sahin, Gurdal

AU - Farran, Aina

AU - Soares, Sofia

AU - Jensen, Poul H

AU - Kirik, Deniz

AU - Romero-Ramos, Marina

PY - 2013/8/13

Y1 - 2013/8/13

N2 - 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.

AB - 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.

U2 - 10.1016/j.nbd.2013.03.014

DO - 10.1016/j.nbd.2013.03.014

M3 - Journal article

C2 - 23567651

SN - 0969-9961

VL - 56

SP - 47

EP - 58

JO - Neurobiology of Disease

JF - Neurobiology of Disease

ER -

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

Abstract

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