Paper
- Alzforum Recommends
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. PubMed.
Recommends
Please login to recommend the paper.
Comments
University of Colorado
This is an interesting study that attempts to get at the underlying mechanism(s) by which mutations in the progranulin gene (PGRN) cause familial Frontotemporal Dementia (FTD). Progranulin encodes an evolutionarily conserved precursor protein that can be proteolytically processed to produce seven distinct granulin peptides. Frontotemporal dementia caused by PGRN mutations is characterized by cytoplasmic TDP-43 inclusions in affected neurons, a pathology that is also seen in sporadic cases of FTD and ALS. PGRN disease mutations are autosomal dominant yet are caused by a loss-of-function, unlike other familial FTD mutations (e.g. in Tau and TDP-43). This result suggests that just having less PGRN is sufficient to cause neurodegeneration. However, having less is different than having none, and extrapolating from complete knockout models could be misleading.
Salazar et al. specifically examined the role of C. elegans progranulin in the toxicity of a transgenic C. elegans model expressing human wild-type TDP-43. As observed by other research groups, expression of human TDP-43 in C. elegans neurons resulted in movement defects. These movement defects were not altered in worms homozygous for a deletion of their endogenous progranulin gene (pgrn-1). Intriguingly, motor defects were enhanced in worms heterozygous for the pgrn-1 deletion (i.e., equivalent to the situation in humans patients). This result suggests that the phenotypic interaction between TDP-43 and PGRN may actually require some progranulin expression. These researchers went on to show that expression of two individual granulin peptides (granulins 2 and 3) could exacerbate TDP-43 toxicity and enhance TDP-43 protein levels, while a third granulin (granulin #1) had no effect.
How can this curious result be explained? The authors suggest that the processing of progranulin might be finely regulated by the ratio of progranulin produced to the proteolytic enzymes that act on it. Theoretically, a reduction of progranulin "substrate" could lead to more or different proteolytic processing if there is no coordinated change in the processing enzymes. It is tempting to speculate that alterations in processing could alter the ratio of full progranulin to granulin or the ratio of individual granulins produced. (Note that in the case of brain-derived neurotrophic growth factor, proBDNF has effects opposite to processed BDNF.) If individual granulins have competing functions (e.g., might granulin 1 oppose the actions of granulins 2 and 3?), changing the ratios of the granulins could have physiological effects that could not be observed in the homozygous deletion strain.
The above hypothesis suggests numerous follow-up experiments. The suite of granulins actually produced in people homozygous or heterozygous for the PGRN gene has yet to be determined, although this research group has now developed an antibody specific for human granulin "E". The C. elegans model should allow combinatorial expression of individual granulins and the identification of regulators of progranulin processing through forward genetic screens. Finally, if the "altered proccessing" model is correct, one might expect genes encoding the relevant processing factors to be fingered in genome-wide association studies of FTD, or possibly directly implicated in familial FTD cases.
View all comments by Chris LinkMake a Comment
To make a comment you must login or register.