title: Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism.
abstract: 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.
authors.affiliation: Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, DC, USA.
authors.forename: Tetyana
authors.initials: T
authors.lastname: Duka
authors.forename: Milan
authors.initials: M
authors.lastname: Rusnak
authors.forename: Robert E
authors.initials: RE
authors.lastname: Drolet
authors.forename: Valeriy
authors.initials: V
authors.lastname: Duka
authors.forename: Christophe
authors.initials: C
authors.lastname: Wersinger
authors.forename: John L
authors.initials: JL
authors.lastname: Goudreau
authors.forename: Anita
authors.initials: A
authors.lastname: Sidhu
mesh_terms: 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*
chemical_list: D051844:alpha-Synuclein; D016875:tau Proteins