RGD Reference Report - Authentically phosphorylated alpha-synuclein at Ser129 accelerates neurodegeneration in a rat model of familial Parkinson's disease. - Rat Genome Database

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Authentically phosphorylated alpha-synuclein at Ser129 accelerates neurodegeneration in a rat model of familial Parkinson's disease.

Authors: Sato, H  Arawaka, S  Hara, S  Fukushima, S  Koga, K  Koyama, S  Kato, T 
Citation: Sato H, etal., J Neurosci. 2011 Nov 16;31(46):16884-94.
RGD ID: 5684916
Pubmed: PMID:22090514   (View Abstract at PubMed)
PMCID: PMC6633319   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.3967-11.2011   (Journal Full-text)

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra (SN) and the appearance of fibrillar aggregates of insoluble alpha-synuclein (alpha-syn) called Lewy bodies (LBs). Approximately 90% of alpha-syn deposited in LBs is phosphorylated at serine 129 (Ser129). In contrast, only 4% of total alpha-syn is phosphorylated in normal brain, suggesting that accumulation of Ser129-phosphorylated alpha-syn is involved in the pathogenesis of PD. However, the role of Ser129 phosphorylation in alpha-syn neurotoxicity remains unclear. In this study, we coexpressed familial PD-linked A53T alpha-syn and G-protein-coupled receptor kinase 6 (GRK6) in the rat SN pars compacta using recombinant adeno-associated virus 2. Coexpression of these proteins yielded abundant Ser129-phosphorylated alpha-syn and significantly exacerbated degeneration of dopaminergic neurons when compared with coexpression of A53T alpha-syn and GFP. Immunohistochemical analysis revealed that Ser129-phosphorylated alpha-syn was preferentially distributed to swollen neurites. However, biochemical analysis showed that the increased expression of Ser129-phosphorylated alpha-syn did not promote accumulation of detergent-insoluble alpha-syn. Coexpression of catalytically inactive K215R mutant GRK6 failed to accelerate A53T alpha-syn-induced degeneration. Furthermore, introducing a phosphorylation-incompetent mutation, S129A, into A53T alpha-syn did not alter the pace of degeneration, even when GRK6 was coexpressed. Our study demonstrates that authentically Ser129-phosphorylated alpha-syn accelerates A53T alpha-syn neurotoxicity without the formation of detergent-insoluble alpha-syn, and suggests that the degenerative process could be constrained by inhibiting the kinase that phosphorylates alpha-syn at Ser129.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Parkinson's disease  IMP 5684916human gene in rat modelRGD 
Parkinson's disease  ISOGRK6 (Homo sapiens)5684916; 5684916human gene in rat modelRGD 

Objects Annotated

Genes (Rattus norvegicus)
Grk6  (G protein-coupled receptor kinase 6)

Genes (Mus musculus)
Grk6  (G protein-coupled receptor kinase 6)

Genes (Homo sapiens)
GRK6  (G protein-coupled receptor kinase 6)


Additional Information