GSK-3β dysregulation contributes to parkinson's-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and α-synuclein.
Aberrant posttranslational modifications (PTMs) of proteins, namely phosphorylation, induce abnormalities in the biological properties of recipient proteins, underlying neurological diseases including Parkinson's disease (PD). Genome-wide studies link genes encoding α-synuclein (α-Syn) and Tau as two of the most important in the genesis of PD. Although several kinases are known to phosphorylate α-Syn and Tau, we focused our analysis on GSK-3β because of its accepted role in phosphorylating Tau and to increasing evidence supporting a strong biophysical relationship between α-Syn and Tau in PD. Therefore, we investigated transgenic mice, which express a point mutant (S9A) of human GSK-3β. GSK-3β-S9A is capable of activation through endogenous natural signaling events, yet is unable to become inactivated through phosphorylation at serine-9. We used behavioral, biochemical, and in vitro analysis to assess the contributions of GSK-3β to both α-Syn and Tau phosphorylation. Behavioral studies revealed progressive age-dependent impairment of motor function, accompanied by loss of tyrosine hydroxylase-positive (TH+ DA-neurons) neurons and dopamine production in the oldest age group. Magnetic resonance imaging revealed deterioration of the substantia nigra in aged mice, a characteristic feature of PD patients. At the molecular level, kinase-active p-GSK-3β-Y216 was seen at all ages throughout the brain, yet elevated levels of p-α-Syn-S129 and p-Tau (S396/404) were found to increase with age exclusively in TH+ DA-neurons of the midbrain. p-GSK-3β-Y216 colocalized with p-Tau and p-α-Syn-S129. In vitro kinase assays showed that recombinant human GSK-3β directly phosphorylated α-Syn at a single site, Ser129, in addition to its known ability to phosphorylate Tau. Moreover, α-Syn and Tau together cooperated with one another to increase the magnitude or rate of phosphorylation of the other by GSK-3β. Together, these data establish a novel upstream role for GSK-3β as one of several kinases associated with PTMs of key proteins known to be causal in PD.
Department of Biochemistry, Georgetown University, Washington, D.C., USA.
J J
JJ
Credle
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Vic, 3010, Australia.
J L
JL
George
Department of Biochemistry, Georgetown University, Washington, D.C., USA.
J
J
Wills
Department of Biochemistry, Georgetown University, Washington, D.C., USA.
V
V
Duka
Department of Biochemistry, Georgetown University, Washington, D.C., USA.
K
K
Shah
Department of Oncology, Georgetown University, Washington, D.C., USA.
Y-C
YC
Lee
Department of Oncology, Georgetown University, Washington, D.C., USA.
O
O
Rodriguez
Department of Neurology, Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, USA.
T
T
Simkins
Department of Biochemistry, Georgetown University, Washington, D.C., USA.
M
M
Winter
Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, 2340, Belgium.
D
D
Moechars
Janssen Research & Development, a division of Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse, 2340, Belgium.
T
T
Steckler
Department of Neurology, Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, USA.
J
J
Goudreau
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Vic, 3010, Australia.
D I
DI
Finkelstein
Department of Biochemistry, Georgetown University, Washington, D.C., USA.
A
A
Sidhu
D000818:Animals; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
C054369:MAPT protein, human; C558298:Mapt protein, mouse; D051844:alpha-Synuclein; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3