RT Journal Article
SR Electronic
T1 The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 9315
OP 9328
DO 10.1523/JNEUROSCI.4808-14.2015
VO 35
IS 25
A1 Salazar, Dominique A.
A1 Butler, Victoria J.
A1 Argouarch, Andrea R.
A1 Hsu, Tsung-Yuan
A1 Mason, Amanda
A1 Nakamura, Ayumi
A1 McCurdy, Helen
A1 Cox, David
A1 Ng, Rachel
A1 Pan, Gloria
A1 Seeley, William W.
A1 Miller, Bruce L.
A1 Kao, Aimee W.
YR 2015
UL http://www.jneurosci.org/content/35/25/9315.abstract
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.