Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism.
Many neurodegenerative diseases associated with functional Tau dysregulation, including Alzheimer's disease (AD) and other tauopathies, also show alpha-synuclein (alpha-Syn) pathology, a protein associated with Parkinson's disease (PD) pathology. Here we show that treatment of primary mesencephalic neurons (48 h) or subchronic treatment of wild-type (WT) mice with the Parkinsonism-inducing neurotoxin MPP+/MPTP, results in selective dose-dependent hyperphosphorylation of Tau at Ser396/404 (PHF-1-reactive Tau, p-Tau), with no changes in pSer202 but with nonspecific increases in pSer262 levels. The presence of alpha-Syn was absolutely mandatory to observe MPP+/MPTP-induced increases in p-Tau levels, since no alterations in p-Tau were seen in transfected cells not expressing alpha-Syn or in alpha-Syn-/- mice. MPP+/MPTP also induced a significant accumulation of alpha-Syn in both mesencephalic neurons and in WT mice striatum. MPTP/MPP+ lead to differential alterations in p-Tau and alpha-Syn levels in a cytoskeleton-bound, vs. a soluble, cytoskeleton-free fraction, inducing their coimmunoprecipitation in the cytoskeleton-free fraction and neuronal soma. Subchronic MPTP exposure increased sarkosyl-insoluble p-Tau in striatum of WT but not alpha-Syn-/- mice. These studies describe a novel mechanism for MPTP neurotoxicity, namely a MPTP-inducible, strictly alpha-Syn-dependent, increased formation of PHF-1-reactive Tau, suggesting convergent overlapping pathways in the genesis of clinically divergent diseases such as AD and PD.
Duka
Tetyana
T
Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, DC, USA.
Rusnak
Milan
M
Drolet
Robert E
RE
Duka
Valeriy
V
Wersinger
Christophe
C
Goudreau
John L
JL
Sidhu
Anita
A
D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D006801:Humans; D020267:MPTP Poisoning / Q000378:metabolism / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D014162:Transfection; D051844:alpha-Synuclein / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D051844:alpha-Synuclein; D016875:tau Proteins