Small but dangerous? Protein cleavage products linked to FTD

Genetic alterations in the progranulin gene (PGRN) have been known to cause FTD since 2006. The mutations act by reducing the production of the progranulin protein by half, but little is known about the biological processes linking loss of progranulin to neuronal death. A new study by Salazar and colleagues suggests it may not be the loss of progranulin that is important, but the loss of smaller fragments of the protein, known as granulins, which is intrinsically linked with disease.

The progranulin protein can be cleaved into smaller granulins, and both the full-length protein and smaller fragments may have important biological functions. In this report, the authors used a worm model (C. Elegans) to investigate whether progranulin and granulins could cause toxicity via TDP-43, the protein that accumulates in the FTD brain. The loss of full-length progranulin had no effect on development or lifespan in the worms. In contrast, when individual granulin peptides were introduced into the worms, their development and growth was altered. Further, granulin expressing worms exhibited lower levels of “thrashing”, indicating that granulins and TDP-43 in combination have a detrimental effect on the nervous system of the animals. The expression of granulins also resulted in an accumulation of TDP-43 as is seen in FTD.

Importantly, the authors were able to observe an accumulation of granulins in human FTD brain showing some conservation of what was observed in worms through to humans. Further studies of the biological and pathological roles of granulins are warranted to understand if granulins could be potential drug targets for FTD.


Salazar DA, Butler VJ, Argouarch AR, Hsu TY, Mason A, Nakamura A, McCurdy H, Cox D, Ng R, Pan G, Seeley WW, Miller BL, Kao AW. The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels. J Neurosci. 2015 Jun 24;35(25):9315-28

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