PT  - JOURNAL ARTICLE
AU  - Salazar, Dominique A.
AU  - Butler, Victoria J.
AU  - Argouarch, Andrea R.
AU  - Hsu, Tsung-Yuan
AU  - Mason, Amanda
AU  - Nakamura, Ayumi
AU  - McCurdy, Helen
AU  - Cox, David
AU  - Ng, Rachel
AU  - Pan, Gloria
AU  - Seeley, William W.
AU  - Miller, Bruce L.
AU  - Kao, Aimee W.
TI  - The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels
AID  - 10.1523/JNEUROSCI.4808-14.2015
DP  - 2015 Jun 24
TA  - The Journal of Neuroscience
PG  - 9315--9328
VI  - 35
IP  - 25
4099  - http://www.jneurosci.org/content/35/25/9315.short
4100  - http://www.jneurosci.org/content/35/25/9315.full
SO  - J. Neurosci.2015 Jun 24; 35
AB  - 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.