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The neurotoxin, MPP+, induces hyperphosphorylation ofTau, in the presence of α-Synuclein, in SH-SY5Y neuroblastoma cells

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Abstract

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.

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Abbreviations

AD:

Alzheimer’s disease

DAT:

dopamine transporter

FTDP-17:

frontotemporal dementia with parkinsonism linked to chromosome 17

hDAT:

human DAT

LBs:

Lewy bodies

MAP:

microtubules-associated protein

MPP+ :

1-methyl-4-phenylpyridinium ion

MPTP:

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

MTT:

3[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide

PD:

Parkinson’s disease

PHF:

paired helical filaments

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  1. Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, 20007, Washington D.C., USA

    Tetyana Duka & Anita Sidhu

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  1. Tetyana Duka
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  2. Anita Sidhu
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Correspondence to Anita Sidhu.

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Duka, T., Sidhu, A. The neurotoxin, MPP+, induces hyperphosphorylation ofTau, in the presence of α-Synuclein, in SH-SY5Y neuroblastoma cells. neurotox res 10, 1–10 (2006). https://doi.org/10.1007/BF03033329

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