title: The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels.
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.
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: Dominique A
authors.identifier: http://orcid.org/0000-0002-6696-7527
authors.initials: DA
authors.lastname: Salazar
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Butler
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Argouarch
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: Tsung-Yuan
authors.initials: TY
authors.lastname: Hsu
authors.affiliation: Gladstone Institutes of Neurological Disease, San Francisco, California 94148.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mason
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: Helen
authors.initials: H
authors.lastname: McCurdy
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: David
authors.initials: D
authors.lastname: Cox
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: Rachel
authors.initials: R
authors.lastname: Ng
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: Gloria
authors.initials: G
authors.lastname: Pan
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: William W
authors.initials: WW
authors.lastname: Seeley
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and.
authors.forename: Bruce L
authors.identifier: http://orcid.org/0000-0002-2152-4220
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Department of Neurology, University of California at San Francisco, San Francisco, California 94158, and akao@memory.ucsf.edu.
authors.forename: Aimee W
authors.identifier: http://orcid.org/0000-0002-7686-7968
authors.initials: AW
authors.lastname: Kao
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D000077153:Progranulins; D060888:Real-Time Polymerase Chain Reaction; D057177:TDP-43 Proteinopathies / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D029961:Zebrafish Proteins; C509429:grna protein, zebrafish
keywords: C. elegans; TDP-43; frontotemporal lobar degeneration; granulin; neurodegenerative disease; progranulin