Format

Send to

Choose Destination
Neurobiol Dis. 2017 Oct;106:14-22. doi: 10.1016/j.nbd.2017.06.012. Epub 2017 Jun 21.

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

Author information

1
Centre for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, 980 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada.
2
Centre for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children's and Women's Hospital, 980 West 28th Avenue, Vancouver, BC V5Z 4H4, Canada; Division of Neurology, Department of Medicine, University of British Columbia Hospital, S 192 - 2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada; Brain Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada. Electronic address: bleavitt@cmmt.ubc.ca.

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 12months 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.

KEYWORDS:

Conditional knockout mice; Frontotemporal lobar degeneration; Nestin; Neuronal ceroid lipofuscinosis; Neuropathology; Progranulin

PMID:
28647554
DOI:
10.1016/j.nbd.2017.06.012
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center