Int J Biol Sci 2011; 7(2):234-243. doi:10.7150/ijbs.7.234

Research Paper

TDP-43 Potentiates Alpha-synuclein Toxicity to Dopaminergic Neurons in Transgenic Mice

Tian Tian1, 2*, Cao Huang1*, Jianbin Tong1, Ming Yang1, Hongxia Zhou1✉, Xu-Gang Xia1

1. Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA 19107, USA
2. Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province 410008, China
*These authors contributed equally to this work.

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Citation:
Tian T, Huang C, Tong J, Yang M, Zhou H, Xia XG. TDP-43 Potentiates Alpha-synuclein Toxicity to Dopaminergic Neurons in Transgenic Mice. Int J Biol Sci 2011; 7(2):234-243. doi:10.7150/ijbs.7.234. Available from http://www.ijbs.com/v07p0234.htm

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Abstract

TDP-43 and α-synuclein are two disease proteins involved in a wide range of neurodegenerative diseases. While TDP-43 proteinopathy is considered a pathologic hallmark of sporadic amyotrophic lateral sclerosis and frontotemporal lobe degeneration, α-synuclein is a major component of Lewy body characteristic of Parkinson's disease. Intriguingly, TDP-43 proteinopathy also coexists with Lewy body and with synucleinopathy in certain disease conditions. Here we reported the effects of TDP-43 on α-synuclein neurotoxicity in transgenic mice. Overexpression of mutant TDP-43 (M337V substitution) in mice caused early death in transgenic founders, but overexpression of normal TDP-43 only induced a moderate loss of cortical neurons in the transgenic mice at advanced ages. Interestingly, concomitant overexpression of normal TDP-43 and mutant α-synuclein caused a more severe loss of dopaminergic neurons in the double transgenic mice as compared to single-gene transgenic mice. TDP-43 potentiated α-synuclein toxicity to dopaminergic neurons in living animals. Our finding provides in vivo evidence suggesting that disease proteins such as TDP-43 and α-synuclein may play a synergistic role in disease induction in neurodegenerative diseases.

Keywords: TDP-43, alpha-synuclein, mice, dopaminergic neuron, Parkinson's disease, frontotemporal lobe degeneration, genetic model