期刊
TOXICOLOGICAL SCIENCES
卷 167, 期 1, 页码 105-115出版社
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfy267
关键词
TDP-43; neurotoxicity; metals; ALS; LLPS; neurodegeneration
类别
资金
- UGC-Raman Fellowship from Government of India
- NIH [ES020395, AG050471, NS089544, AG056318]
- BrightFocus Foundation
- Alzheimer Association
- Cure Alzheimer's Fund
- Thome Memorial Foundation
Heavy metals, such as lead, mercury, and selenium, have been epidemiologically linked with a risk of ALS, but a molecular mechanism proving the connection has not been shown. A screen of putative developmental neurotoxins demonstrated that heavy metals (lead, mercury, and tin) trigger accumulation of TDP-43 into nuclear granules with concomitant loss of diffuse nuclear TDP-43. Lead (Pb) and methyl mercury (MeHg) disrupt the homeostasis of TDP-43 in neurons, resulting in increased levels of transcript and increased splicing activity of TDP-43. TDP-43 homeostasis is tightly regulated, and positively or negatively altering its splicing-suppressive activity has been shown to be deleterious to neurons. These changes are associated with the liquid-liquid phase separation of TDP-43 into nuclear bodies. We show that lead directly facilitates phase separation of TDP-43 in a dose-dependent manner in vitro, possibly explaining the means by which lead treatment results in neuronal nuclear granules. Metal toxicants also triggered the accumulation of insoluble TDP-43 in cultured cells and in the cortices of exposed mice. These results provide novel evidence of a direct mechanistic link between heavy metals, which are a commonly cited environmental risk of ALS, and molecular changes in TDP-43, the primary pathological protein accumulating in ALS.
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