The neurotoxin, MPP+, induces hyperphosphorylation ofTau, in the presence of α-Synuclein, in SH-SY5Y neuroblastoma cells
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- Duka, T. & Sidhu, A. neurotox res (2006) 10: 1. doi:10.1007/BF03033329
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Alzheimer’s disease (AD) is characterized, in part, by intracellular neurofibrillary tangles composed of hyperphosphorylated filamentous aggregates of the microtubule-associated protein,Tau. Such hyperphosphorylatedTau is also found in Lewy bodies (LBs), and cytoplasmic inclusion bodies in certain forms of Parkinson’s disease (PD). Further, LBs also contain aggregates of α-synuclein (α-Syn), also a microtubule-associated protein, which has been linked to the genesis of PD. To investigate a specific correlation betweenTau phosphorylation and α-Syn, we generated a SH-SY5Y cell line that stably expresses human wild type α-Syn. Protein expression levels in the stably transfected cell line (SHα-Syn) were within the physiological range of α-Syn expression found inSubstantia nigra. We show here, in the MPP+ (1-methyl-4-phenylpyridinium ion) cell model of parkinsonism, a time- and dose-dependent increase in the hyperphosphorylation ofTau at pSer396/404 (PHF-1-reactiveTau, p-Tau), concomitant with increased accumulation of α-Syn, upon treatment of cells with the neurotoxin. This increase in p-Tau was strictly dependent on the presence of α-Syn, since in transfected cells not expressing any α-Syn, MPP+ failed to induce an increase in PHF-1-reactiveTau. The production ofp- Tau caused increased cytotoxicity as indexed by reduced cell viability. Moreover, in the absence of α-Syn, the cells were more resistant to MPP+-induced cell death. The increased levels of both p-Tau and α-Syn led to diminished levels of these proteins associated with the cytoskeleton, which was accompanied by enhanced presence of the proteins in the cytoskeletal-free fractions. These data indicate that α-Syn and p-Tau modulate the pathogenicity of one another, suggesting a novel convergent mechanism of neurodegeneration.
KeywordsParkinson’s disease Alzheimer’s disease Lewy bodies a-Synuclein p-Tau MPTP
frontotemporal dementia with parkinsonism linked to chromosome 17
paired helical filaments