April 2012

Worm protein provides insight into aging and neurodegeneration

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Humans carry an RNA-processing protein called the transactive response DNA-binding protein, or TARDBP/TDP-43. The protein has been linked to a number of neurodegenerative disorders that involve protein misfolding, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. In a recent “Paper of the Week” published in the Journal of Biological Chemistry, Jiou Wang at The Johns Hopkins University and colleagues described a Caenorhabditis elegans model in which they removed the worm version of the TDP-43 protein, called TDP-1 (1).

Why the worm? “Although mammals such as mice offer important models for human diseases, sometimes the complexity of the mammalian systems prevent the unraveling of basic functions of a molecule,” explains Wang. “For example, the TDP-43 knockout mice die in early embryogenesis, making it difficult to tease out the physiological functions of the protein.”

Wang’s team showed that the worm and human versions of the RNA-processing protein were very similar. Worms missing TDP-1 suffered from problems with fertility, growth and movement, but, intriguingly, they lived longer. The mutant worms were also more resilient against the toxic effects of misfolded proteins. The investigators concluded that TDP-1 regulates protein homeostasis and aging through RNA processing.

Because protein homeostasis and aging are common themes in many age-dependent neurodegenerative diseases, “we are hopeful that interventions that improve protein homeostasis or delay aging might eventually turn out to be effective strategies to treat these devastating conditions,” says Wang. But, he cautions, first “we need to learn more about normal functions of TDP-43.”

Reference
  1. 1. Zhang, Tao et al. J. Biol. Chem. 11, 8371 – 8382 (2012).

Rajendrani Mukhopadhyay (rmukhopadhyay@asbmb.org) is the senior science writer for ASBMB Today and the technical editor for the Journal of Biological Chemistry.


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