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J Neurosci. 2015 Jun 24;35(25):9315-28. doi: 10.1523/JNEUROSCI.4808-14.2015.

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

Author information

1
Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
2
Gladstone Institutes of Neurological Disease, San Francisco, California 94148.
3
Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and akao@memory.ucsf.edu.

Abstract

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.

KEYWORDS:

C. elegans; TDP-43; frontotemporal lobar degeneration; granulin; neurodegenerative disease; progranulin

PMID:
26109656
PMCID:
PMC4478251
DOI:
10.1523/JNEUROSCI.4808-14.2015
[Indexed for MEDLINE]
Free PMC Article

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