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PMID:17077307
| Citation |
Duka, T, Rusnak, M, Drolet, RE, Duka, V, Wersinger, C, Goudreau, JL and Sidhu, A (2006) Alpha-synuclein induces hyperphosphorylation of Tau in the MPTP model of parkinsonism. FASEB J. 20:2302-12 |
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| 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. |
| Links |
PubMed Online version:10.1096/fj.06-6092com |
| Keywords |
Animals; Cell Line; Cloning, Molecular; Disease Models, Animal; Humans; MPTP Poisoning/metabolism; MPTP Poisoning/physiopathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphorylation; Transfection; alpha-Synuclein/deficiency; alpha-Synuclein/genetics; alpha-Synuclein/metabolism; tau Proteins/metabolism |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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