Specificity and Regulation of Casein Kinase-Mediated Phosphorylation of α-Synuclein

2008/05/01 by Elisa A. Waxman, Benoit I. Giasson · 207 citations
Medicine · Neuroscience · #Alpha (finance) #Alpha-synuclein #Alzheimer's disease research and treatments #Biochemistry #Biology #Casein kinase 1 #Casein kinase 2 #Cell biology #Cyclin-dependent kinase 2 #Dementia #Dementia with Lewy bodies #Dephosphorylation #Disease #Gene #Genetically modified mouse #Hyperphosphorylation #In vitro #Kinase #Medicine #Molecular biology #Neurological diseases and metabolism #Parkinson's Disease Mechanisms and Treatments #Parkinson's disease #Pathology #Phosphatase #Phosphorylation #Protein kinase A #Synucleinopathies #Transgene

paper · pdf · doi:10.1097/nen.0b013e3186fc995

published in Journal of Neuropathology & Experimental Neurology 67(5), 402-416 (Oxford University Press)

openalex publication_date 2008/05/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/04

Abstract

alpha-Synuclein (alpha-syn) is the major component of pathologic inclusions that characterize neurodegenerative disorders such as Parkinson disease, dementia with Lewy body disease, and multiple system atrophy. The present study uses novel phospho-specific antibodies to assess the presence and regulation of phosphorylated Ser87 and Ser129 in alpha-syn in human brain samples and in a transgenic mouse model of alpha-synucleinopathies. By immunohistochemistry, alpha-syn phosphorylated at Ser129, but not at Ser87, was abundant in alpha-syn inclusions. Under normal conditions, Ser129 phosphorylation, but not Ser87 phosphorylation, was detected at low levels in the soluble biochemical fractions in human alpha-syn transgenic mice and stably transfected cultured cells. Therefore, a role for Ser87 phosphorylation in alpha-synucleinopathies is unlikely, and in vitro assays showed that phosphorylation at this site would inhibit polymerization. In vitro studies also indicated that hyperphosphorylation of Ser129 alpha-syn in pathologic inclusions may be due in part to the intrinsic properties of aggregated alpha-syn to act as substrates for kinases but not phosphatases. Further studies in transgenic mice and cultured cells suggest that cellular toxicity, including proteasomal dysfunction, increases casein kinase 2 activity, which results in elevated Ser129 alpha-syn phosphorylation. These data provide novel explanations for the presence of hyperphosphorylated Ser129 alpha-syn in pathologic inclusions.

Citations

• Ubiquitination of α-Synuclein in Lewy Bodies Is a Pathological Event Not Associated with Impairment of Proteasome Function
• The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Cited by

• Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission
• Protein kinases CK1 and CK2 as new targets for neurodegenerative diseases
• Phosphorylation of synucleins by members of the Polo-like kinase family. [europepmc]
• Phosphorylation at S87 is enhanced in synucleinopathies, inhibits alpha-synuclein oligomerization, and influences synuclein-membrane interactions. [europepmc]
• Serine 129 phosphorylation reduces the ability of alpha-synuclein to regulate tyrosine hydroxylase and protein phosphatase 2A in vitro and in vivo. [europepmc]
• A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. [europepmc]
• Induction of intracellular tau aggregation is promoted by α-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. [europepmc]
• α-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies. [europepmc]
• Mimicking phosphorylation at serine 87 inhibits the aggregation of human α-synuclein and protects against its toxicity in a rat model of Parkinson's disease. [europepmc]
• Phosphorylated α-synuclein in Parkinson's disease. [europepmc]
• Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. [europepmc]
• Systematic mutagenesis of α-synuclein reveals distinct sequence requirements for physiological and pathological activities. [europepmc]
• Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. [europepmc]
• Changes in properties of serine 129 phosphorylated α-synuclein with progression of Lewy-type histopathology in human brains. [europepmc]
• α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson's disease and multiple system atrophy? [europepmc]
• Amyloidogenic α-synuclein seeds do not invariably induce rapid, widespread pathology in mice. [europepmc]
• Protein phosphorylation in neurodegeneration: friend or foe? [europepmc]
• Α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. [europepmc]
• Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer's disease or corticobasal degeneration brains. [europepmc]
• Progressive aggregation of alpha-synuclein and selective degeneration of lewy inclusion-bearing neurons in a mouse model of parkinsonism. [europepmc]
• Propagation of alpha-synuclein pathology: hypotheses, discoveries, and yet unresolved questions from experimental and human brain studies. [europepmc]
• G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons. [europepmc]
• Cell Biology and Pathophysiology of α-Synuclein. [europepmc]
• Mechanisms underlying extensive Ser129-phosphorylation in α-synuclein aggregates. [europepmc]
• Induction of alpha-synuclein pathology in the enteric nervous system of the rat and non-human primate results in gastrointestinal dysmotility and transient CNS pathology. [europepmc]
• Phosphorylated α-synuclein in the retina is a biomarker of Parkinson's disease pathology severity. [europepmc]
• A growth-factor-activated lysosomal K + channel regulates Parkinson's pathology. [europepmc]

Related

• Polo-like kinase inhibition leads to neuroprotection of neurons bearing alpha-synuclein Lewy body-like inclusions in vivo
• Novel tools to quantify total, phospho-Ser129 and aggregated alpha-synuclein in the mouse brain
• Ubiquitination of α-Synuclein in Lewy Bodies Is a Pathological Event Not Associated with Impairment of Proteasome Function
• Hsp70 Reduces α-Synuclein Aggregation and Toxicity
• Sorting out release, uptake and processing of alpha‐synuclein during prion‐like spread of pathology