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

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
GRK6HumanParkinson's disease  IMP human gene in rat modelRGD 
Grk6RatParkinson's disease  ISOGRK6 (Homo sapiens)human gene in rat modelRGD 
Grk6MouseParkinson's disease  ISOGRK6 (Homo sapiens)human 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