For COVID-19 vaccine updates, please review our information guide. For patient eligibility and scheduling availability, please visit VaccineTogetherNY.org.

Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury.

TitleProgranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury.
Publication TypeJournal Article
Year of Publication2012
AuthorsMartens LHerl, Zhang J, Barmada SJ, Zhou P, Kamiya S, Sun B, Min S-W, Gan L, Finkbeiner S, Huang EJ, Farese RV
JournalJ Clin Invest
Volume122
Issue11
Pagination3955-9
Date Published2012 Nov
ISSN1558-8238
Keywords1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Animals, Cell Death, Cells, Cultured, Cerebral Cortex, Frontotemporal Dementia, Humans, Inflammation, Intercellular Signaling Peptides and Proteins, Interferon-gamma, Lipopolysaccharides, Mice, Mice, Knockout, Microglia, MPTP Poisoning, Nerve Tissue Proteins, Neurons, Neurotoxins
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 (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.

DOI10.1172/JCI63113
Alternate JournalJ. Clin. Invest.
PubMed ID23041626
PubMed Central IDPMC3484443
Grant ListP50 AG023501 / AG / NIA NIH HHS / United States
I01 BX001108 / BX / BLRD VA / United States
GMO 100909 / / PHS HHS / United States
R01 AG036884 / AG / NIA NIH HHS / United States
R01 NS039074 / NS / NINDS NIH HHS / United States
RR18928 / RR / NCRR NIH HHS / United States
K08 NS072233 / NS / NINDS NIH HHS / United States
R01 AG030207 / AG / NIA NIH HHS / United States
K26 OD010927 / OD / NIH HHS / United States
P01 AG022074 / AG / NIA NIH HHS / United States
F31 AG034793 / AG / NIA NIH HHS / United States
C06 RR018928 / RR / NCRR NIH HHS / United States