The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels

• Published in: The Journal of neuroscience Vol. 35; no. 25; pp. 9315 - 9328
• Main Authors: Salazar, D. A., Butler, V. J., Argouarch, A. R., Hsu, T.-Y., Mason, A., Nakamura, A., McCurdy, H., Cox, D., Ng, R., Pan, G., Seeley, W. W., Miller, B. L., Kao, A. W.
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 24.06.2015
• Subjects: Animals; Animals, Genetically Modified; Caenorhabditis elegans; Disease Models, Animal; DNA-Binding Proteins - metabolism; Humans; Immunoblotting; Intercellular Signaling Peptides and Proteins - metabolism; Real-Time Polymerase Chain Reaction; TDP-43 Proteinopathies - metabolism; Zebrafish Proteins - metabolism; progranulin; C. elegans; neurodegenerative disease; TDP-43; frontotemporal lobar degeneration; granulin
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4808-14.2015

Mutations in the human progranulin gene resulting in protein haploinsufficiency cause frontotemporal lobar degeneration with TDP-43 inclusions. Although progress has been made in understanding the normal functions of progranulin and TDP-43, the molecular interactions between these proteins remain unclear. Progranulin is proteolytically processed into granulins, but the role of granulins in the pathogenesis of neurodegenerative disease is unknown. We used a Caenorhabditis elegans model of neuronal TDP-43 proteinopathy to specifically interrogate the contribution of granulins to the neurodegenerative process. Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did. Interestingly, expression of individual granulins alone had little effect on behavior. In contrast, when granulins were coexpressed with TDP-43, they exacerbated its toxicity in a variety of behaviors including motor coordination. These same granulins increased TDP-43 levels via a post-translational mechanism. We further found that in human neurodegenerative disease subjects, granulin fragments accumulated specifically in diseased regions of brain. To our knowledge, this is the first demonstration of a toxic role for granulin fragments in a neurodegenerative disease model. These studies suggest that presence of cleaved granulins, rather than or in addition to loss of full-length progranulin, may contribute to disease in TDP-43 proteinopathies.