期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 7, 期 2, 页码 234-243出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.7.234
关键词
TDP-43; alpha-synuclein; mice; dopaminergic neuron; Parkinson's disease; frontotemporal lobe degeneration; genetic model
资金
- National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke [NS064042, NS072113]
- National Institutes of Health/National Institute of Environmental Health Sciences [ES016760]
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [R01ES016760] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS064042, R01NS072113] Funding Source: NIH RePORTER
TDP-43 and alpha-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, alpha-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 a-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 alpha-synuclein caused a more severe loss of dopaminergic neurons in the double transgenic mice as compared to single-gene transgenic mice. TDP-43 potentiated alpha-synuclein toxicity to dopaminergic neurons in living animals. Our finding provides in vivo evidence suggesting that disease proteins such as TDP-43 and alpha-synuclein may play a synergistic role in disease induction in neurodegenerative diseases.
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