Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury.
J Clin Invest
; 122(11): 3955-9, 2012 11.
Article
en En
| MEDLINE
| ID: mdl-23041626
ABSTRACT
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 (Grnâ»/â») showed more neuron loss and increased microgliosis compared with wild-type mice. The exacerbated neuron loss was due not to selective vulnerability of Grnâ»/â» 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 Grnâ»/â» 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, Grnâ»/â» 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.
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Base de datos:
MEDLINE
Asunto principal:
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina
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Microglía
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Intoxicación por MPTP
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Péptidos y Proteínas de Señalización Intercelular
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Proteínas del Tejido Nervioso
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Neuronas
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Neurotoxinas
Idioma:
En
Revista:
J Clin Invest
Año:
2012
Tipo del documento:
Article