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Core neuropathological abnormalities in progranulin-deficient mice are penetrant on multiple genetic backgrounds
T L Petkau1, A Hill1, B R Leavitt2
1Center 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.
Neuroscience
|December 25, 2015
Summary
Progranulin gene mutations cause frontotemporal lobar degeneration. Genetic background influences neuroinflammation and brain changes in progranulin-knockout mice, impacting disease presentation.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- Loss-of-function mutations in the progranulin gene (GRN) are a common cause of familial frontotemporal lobar degeneration (FTLD).
- FTLD exhibits significant heterogeneity in onset, duration, and clinical presentation, even within families with identical GRN mutations, suggesting genetic modifiers.
- Progranulin-knockout mice show subtle behavioral and neuropathological changes, including hippocampal synaptic deficits.
Purpose of the Study:
- To investigate the impact of genetic background on progranulin-mediated neuropathological phenotypes.
- To evaluate neuroinflammation and hippocampal alterations in progranulin-knockout mice on different genetic backgrounds.
Main Methods:
- Aged progranulin knockout mice and wild-type littermates on C57Bl/6 and 129/SvImJ genetic backgrounds were analyzed.
- Neuropathological endpoints including astrogliosis, microgliosis, lipofuscin deposition, and hippocampal neuron counts/morphology were assessed.
Main Results:
- Both mouse strains exhibited progranulin-deficiency-related neuropathology, including neuroinflammation and accelerated lipofuscin deposition.
- Neuroinflammation was more severe in the C57Bl/6 strain compared to the 129/SvImJ strain.
- Strain-dependent differences were observed in hippocampal neuron counts and morphology, indicating a complex role for progranulin in this region.
Conclusions:
- Core neurodegenerative phenotypes associated with progranulin deficiency are present across different inbred mouse strains.
- Genetic background significantly modulates the severity of neuroinflammation and the specific roles of progranulin in hippocampal biology.
