Document Detail

Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury.
MedLine Citation:
PMID:  23041626     Owner:  NLM     Status:  MEDLINE    
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.
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
Related Documents :
23623886 - Optogenetics in the cerebellum: purkinje cell-specific approaches for understanding loc...
24431386 - Brain regional vulnerability to anaesthesia-induced neuroapoptosis shifts with age at e...
24998526 - Regulation of neuronal migration by dchs1-fat4 planar cell polarity.
23850686 - Information processing in brainstem bitter taste-relaying neurons defined by genetic tr...
10638816 - Detecting unitary events without discretization of time.
15312966 - Hippocampal neurons in pre-clinical alzheimer's disease.
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    
Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / adverse effects*,  pharmacology
Cell Death / drug effects,  genetics
Cells, Cultured
Cerebral Cortex / metabolism,  pathology
Frontotemporal Dementia / genetics,  metabolism,  pathology
Inflammation / chemically induced,  genetics,  metabolism,  pathology
Intercellular Signaling Peptides and Proteins / genetics,  metabolism*
Interferon-gamma / pharmacology
Lipopolysaccharides / pharmacology
MPTP Poisoning / genetics,  metabolism*,  pathology
Mice, Knockout
Microglia / metabolism*,  pathology
Nerve Tissue Proteins / genetics,  metabolism*
Neurons / metabolism*,  pathology
Neurotoxins / adverse effects*,  pharmacology
Grant Support
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
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

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  The bitter taste of infection.
Next Document:  Adipocyte-derived endotrophin promotes malignant tumor progression.