RRC ID |
45638
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著者 |
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.
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タイトル |
The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels.
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ジャーナル |
J Neurosci
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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.
|
巻・号 |
35(25)
|
ページ |
9315-28
|
公開日 |
2015-6-24
|
DOI |
10.1523/JNEUROSCI.4808-14.2015
|
PII |
35/25/9315
|
PMID |
26109656
|
PMC |
PMC4478251
|
MeSH |
Animals
Animals, Genetically Modified
Caenorhabditis elegans
DNA-Binding Proteins / metabolism*
Disease Models, Animal
Humans
Immunoblotting
Intercellular Signaling Peptides and Proteins / metabolism*
Progranulins
Real-Time Polymerase Chain Reaction
TDP-43 Proteinopathies / metabolism*
Zebrafish Proteins / metabolism
|
IF |
5.674
|
引用数 |
27
|
WOS 分野
|
NEUROSCIENCES
|
リソース情報 |
線虫 |
tm985 |