Document Detail


Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury.
MedLine Citation:
PMID:  23041626     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Progranulin (PGRN) is a widely expressed secreted protein that is linked to inflammation. In humans, PGRN haploinsufficiency is a major inherited cause of frontotemporal dementia (FTD), but how PGRN deficiency causes neurodegeneration is unknown. Here we show that loss of PGRN results in increased neuron loss in response to injury in the CNS. When exposed acutely to 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydrophine (MPTP), mice lacking PGRN (Grn⁻/⁻) showed more neuron loss and increased microgliosis compared with wild-type mice. The exacerbated neuron loss was due not to selective vulnerability of Grn⁻/⁻ neurons to MPTP, but rather to an increased microglial inflammatory response. Consistent with this, conditional mutants lacking PGRN in microglia exhibited MPTP-induced phenotypes similar to Grn⁻/⁻ mice. Selective depletion of PGRN from microglia in mixed cortical cultures resulted in increased death of wild-type neurons in the absence of injury. Furthermore, Grn⁻/⁻ microglia treated with LPS/IFN-γ exhibited an amplified inflammatory response, and conditioned media from these microglia promoted death of cultured neurons. Our results indicate that PGRN deficiency leads to dysregulated microglial activation and thereby contributes to increased neuron loss with injury. These findings suggest that PGRN deficiency may cause increased neuron loss in other forms of CNS injury accompanied by neuroinflammation.
Authors:
Lauren Herl Martens; Jiasheng Zhang; Sami J Barmada; Ping Zhou; Sherry Kamiya; Binggui Sun; Sang-Won Min; Li Gan; Steven Finkbeiner; Eric J Huang; Robert V Farese
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-10-08
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-01     Completed Date:  2013-01-15     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3955-9     Citation Subset:  AIM; IM    
Affiliation:
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
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MeSH Terms
Descriptor/Qualifier:
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / adverse effects*,  pharmacology
Animals
Cell Death / drug effects,  genetics
Cells, Cultured
Cerebral Cortex / metabolism,  pathology
Frontotemporal Dementia / genetics,  metabolism,  pathology
Humans
Inflammation / chemically induced,  genetics,  metabolism,  pathology
Intercellular Signaling Peptides and Proteins / genetics,  metabolism*
Interferon-gamma / pharmacology
Lipopolysaccharides / pharmacology
MPTP Poisoning / genetics,  metabolism*,  pathology
Mice
Mice, Knockout
Microglia / metabolism*,  pathology
Nerve Tissue Proteins / genetics,  metabolism*
Neurons / metabolism*,  pathology
Neurotoxins / adverse effects*,  pharmacology
Grant Support
ID/Acronym/Agency:
F31 AG034793/AG/NIA NIH HHS; GMO 100909//PHS HHS; K08 NS072233/NS/NINDS NIH HHS; K08 NS072233/NS/NINDS NIH HHS; K26 OD010927/OD/NIH HHS; P01 AG022074/AG/NIA NIH HHS; P50 AG023501/AG/NIA NIH HHS; R01 AG030207/AG/NIA NIH HHS; RR18928/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Grn protein, mouse; 0/Intercellular Signaling Peptides and Proteins; 0/Lipopolysaccharides; 0/Nerve Tissue Proteins; 0/Neurotoxins; 28289-54-5/1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 82115-62-6/Interferon-gamma
Comments/Corrections

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