title: TDP-43 potentiates alpha-synuclein toxicity to dopaminergic neurons in transgenic mice.
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.
authors: Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors: Tian
authors: T
authors: Tian
authors: Cao
authors: C
authors: Huang
authors: Jianbin
authors: J
authors: Tong
authors: Ming
authors: M
authors: Yang
authors: Hongxia
authors: H
authors: Zhou
authors: Xu-Gang
authors: XG
authors: Xia
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D051844:alpha-Synuclein; D004298:Dopamine