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Alpha-Synuclein Induces Hyperphosphorylation of Au in the Mptp Model of Parkinsonism

Tetyana Duka^*, Milan Rusnak^*, Robert E. Drolet, Valeriy Duka^*, Christophe Wersinger^*, John L. Goudreau and Anita Sidhu^*,1

^* Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, DC, USA; and

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA

¹Correspondence: Head, Laboratory of Molecular Neurochemistry, The Research Bldg., Rm. W222, 3970 Reservoir Rd., NW, Washington, DC. 20007. E-mail: sidhua{at}georgetown.edu

Many neurodegenerative diseases associated with functional Tau dysregulation, including Alzheimer’s disease (AD) and other tauopathies, also show -synuclein (-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 -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 -Syn or in -Syn–/– mice. MPP⁺/MPTP also induced a significant accumulation of -Syn in both mesencephalic neurons and in WT mice striatum. MPTP/MPP⁺ lead to differential alterations in p-Tau and -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 -Syn–/– mice. These studies describe a novel mechanism for MPTP neurotoxicity, namely a MPTP-inducible, strictly -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, T., Rusnak, M., Drolet, R. E., Duka, V., Wersinger, C., Goudreau, J. L., Sidhu, A. Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of Parkinsonism.

Key Words: PD • Alzheimer’s disease • mesencephalic neurons • -synuclein knock-out mice • neurodegeneration