Tau knockout exacerbates degeneration of parvalbumin-positive neurons in substantia nigra pars reticulata in Parkinson's disease-related α-synuclein A53T mice.

Luyan Jiao, Meige Zheng, Jinhai Duan, Ting Wu, Zhao Li, Lin Liu, Xianhong Xiang, Xiaolu Tang, Jinyang He, Xingjian Li, Guofeng Zhang, Jinhui Ding, Huaibin Cai, Xian Lin

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2020 Sep

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α-Synuclein (α-syn)-induced neurotoxicity has been generally accepted as a key step in the pathogenesis of Parkinson's disease (PD). Microtubule-associated protein tau, which is considered second only to α-syn, has been repeatedly linked with PD in association studies. However, the underlying interaction between these two PD-related proteins in vivo remains unclear. To investigate how the expression of tau affects α-syn-induced neurodegeneration in vivo, we generated triple transgenic mice that overexpressed α-syn A53T mutation in the midbrain dopaminergic neurons (mDANs) with different expression levels of tau. Here, we found that tau had no significant effect on the A53T α-syn-mediated mDANs degeneration. However, tau knockout could modestly promote the formation of α-syn aggregates, accelerate the severe and progressive degeneration of parvalbumin-positive (PV+) neurons in substantia nigra pars reticulata (SNR), accompanied with anxiety-like behavior in aged PD-related α-syn A53T mice. The mechanisms may be associated with A53T α-syn-mediated specifically successive impairment of N-methyl-d-aspartate receptor subunit 2B (NR2B), postsynaptic density-95 (PSD-95) and microtubule-associated protein 1A (MAP1A) in PV+ neurons. Our study indicates that MAP1A may play a beneficial role in preserving the survival of PV+ neurons, and that inhibition of the impairment of NR2B/PSD-95/MAP1A pathway, may be a novel and preferential option to ameliorate α-syn-induced neurodegeneration. © 2020 Federation of American Societies for Experimental Biology.

Citation

Luyan Jiao, Meige Zheng, Jinhai Duan, Ting Wu, Zhao Li, Lin Liu, Xianhong Xiang, Xiaolu Tang, Jinyang He, Xingjian Li, Guofeng Zhang, Jinhui Ding, Huaibin Cai, Xian Lin. Tau knockout exacerbates degeneration of parvalbumin-positive neurons in substantia nigra pars reticulata in Parkinson's disease-related α-synuclein A53T mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Sep;34(9):12239-12254