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Alpha‐Synuclein induces hyperphosphorylation of Tau in the MPTP model of Parkinsonism
Author(s) -
Duka Tetyana,
Rusnak Milan,
Drolet Robert E.,
Duka Valeriy,
Wersinger Christophe,
Goudreau John L.,
Sidhu Anita
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-6092com
Subject(s) - mptp , hyperphosphorylation , alpha synuclein , parkinsonism , striatum , neurotoxin , chemistry , neurotoxicity , tau protein , substantia nigra , dopaminergic , medicine , endocrinology , parkinson's disease , neuroscience , dopamine , biology , alzheimer's disease , toxicity , biochemistry , phosphorylation , disease
Many neurodegenerative diseases associated with functional Tau dysregulation, including Alzheimer's disease (AD) and other tauopathies, also show α‐synuclein (α‐ 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 α ‐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 α ‐Syn or in α ‐Syn ‐ / ‐ mice. MPP + /MPTP also induced a significant accumulation of α ‐Syn in both mesencephalic neurons and in WT mice striatum. MPTP/MPP + lead to differential alterations in p‐ Tau and α ‐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 α ‐Syn ‐ / ‐ mice. These studies describe a novel mechanism for MPTP neurotoxicity, namely a MPTP‐inducible, strictly α ‐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. FASEB J. 20, 2302–2312 (2006)