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10.1523/JNEUROSCI.4808-14.2015

http://scihub22266oqcxt.onion/10.1523/JNEUROSCI.4808-14.2015
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C4478251!4478251!26109656
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suck abstract from ncbi


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pmid26109656      J+Neurosci 2015 ; 35 (25): 9315-28
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  • The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels #MMPMID26109656
  • Salazar DA; Butler VJ; Argouarch AR; Hsu TY; Mason A; Nakamura A; McCurdy H; Cox D; Ng R; Pan G; Seeley WW; Miller BL; Kao AW
  • J Neurosci 2015[Jun]; 35 (25): 9315-28 PMID26109656show ga
  • 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.
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