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Neurobiology of Disease
Article . 2017 . Peer-reviewed
License: Elsevier TDM
Data sources: Crossref
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Article . 2017
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Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice

Authors: Terri L. Petkau; Jake Blanco; Blair R. Leavitt;

Conditional loss of progranulin in neurons is not sufficient to cause neuronal ceroid lipofuscinosis-like neuropathology in mice

Abstract

Progranulin deficiency due to heterozygous null mutations in the GRN gene is a common cause of familial frontotemporal lobar degeneration (FTLD), while homozygous loss-of-function GRN mutations cause neuronal ceroid lipofuscinosis (NCL). Aged progranulin-knockout mice display highly exaggerated lipofuscinosis, microgliosis, and astrogliosis, as well as mild cell loss in specific brain regions. Progranulin is a secreted glycoprotein expressed in both neurons and microglia, but not astrocytes, in the brain. We generated conditional progranulin-knockout mice that lack progranulin in nestin-expressing cells (Nes-cKO mice), which include most neurons as well as astrocytes. We confirmed near complete knockout of progranulin in neurons in Nes-cKO mice, while microglial progranulin levels remained similar to that of wild-type animals. Overall brain progranulin levels were reduced by about 50% in Nes-cKO, and no Grn was detected in primary Nes-cKO neurons. Nes-cKO mice aged to 12 months did not display any increase in lipofuscin deposition, microgliosis, or astrogliosis in the four brain regions examined, though increases were observed for most of these measures in Grn-null animals. We conclude that neuron-specific loss of progranulin is not sufficient to cause similar neuropathological changes to those seen in constitutive Grn-null animals. Our results suggest that increased lipofuscinosis and gliosis in Grn-null animals are not caused by intrinsic progranulin deficiency in neurons, and that microglia-derived progranulin may be sufficient to maintain neuronal health and homeostasis in the brain.

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Subjects by Vocabulary

Microsoft Academic Graph classification: Pathology medicine.medical_specialty Neuropathology Biology Microgliosis Lipofuscin medicine Microglia Frontotemporal lobar degeneration medicine.disease Astrogliosis medicine.anatomical_structure Gliosis Neuronal ceroid lipofuscinosis medicine.symptom

Library of Congress Subject Headings: lcsh:RC321-571 lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry

Keywords

Progranulin, Frontotemporal lobar degeneration, Lipofuscin, Nestin, Progranulins, Neuronal Ceroid-Lipofuscinoses, Animals, Gliosis, RNA, Messenger, Neuropathology, Granulins, Mice, Knockout, Neurons, Calcium-Binding Proteins, Microfilament Proteins, Brain, Conditional knockout mice, Neuronal ceroid lipofuscinosis, Mice, Inbred C57BL, Disease Models, Animal, Phenotype, Neurology, Astrocytes, Intercellular Signaling Peptides and Proteins, Microglia

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    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    19
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Average
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
  • citations
    This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    19
    popularity
    This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
    Top 10%
    influence
    This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
    Average
    impulse
    This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
    Top 10%
    Powered byBIP!BIP!
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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
19
Top 10%
Average
Top 10%
gold
Funded by
CIHR
Project
  • Funder: Canadian Institutes of Health Research (CIHR)
Related to Research communities
Neuroinformatics
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