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Microglial upregulation of progranulin as a marker of motor neuron degeneration
Thomas Philips1, Louis De Muynck, Hoai Nguyen Thi Thu
1Vesalius Research Center, VIB, Leuven, Belgium.
Abstract:
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are overlapping neurodegenerative disorders. Mutations in the growth factor progranulin (PGRN) gene cause FTLD, sometimes in conjunction with ALS; such mutations are also observed in some ALS patients. Most PGRN mutations underlying FTLD are null mutations that result in reduced PGRN levels. We investigated PGRN expression in human ALS and in mouse models of motor neuron degeneration. Progranulin plasma or CSF levels in newly diagnosed ALS patients did not differ from those in healthy or disease controls (PGRN mutation-negative FTLD and Alzheimer disease patients). In the mutant SOD1 mouse model of ALS, spinal cord PGRN levels were normal in presymptomatic animals but increased during the degenerative process. This increase in PGRN correlated with enhanced expression of PGRN in microglia. In CSF, PGRN levels were normal in presymptomatic and early symptomatic animals, but with disease progression, a raise in PGRN was detectable. These data indicate that upregulation of PGRN is a marker of the microglial response that occurs with progression in motor neuron diseases.
Insights
Upregulation of progranulin (PGRN) indicates a microglial response in motor neuron diseases like ALS. PGRN levels increase during disease progression in mouse models, suggesting it
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are related neurodegenerative disorders.
- Progranulin (PGRN) gene mutations cause FTLD and are sometimes found in ALS patients, typically leading to reduced PGRN levels.
Purpose of the Study:
- To investigate progranulin (PGRN) expression in human ALS and mouse models of motor neuron degeneration.
- To determine if PGRN levels change during the progression of motor neuron diseases.
Main Methods:
- Measured progranulin (PGRN) levels in plasma and cerebrospinal fluid (CSF) of human ALS patients and controls.
- Assessed PGRN expression in the spinal cord and CSF of a mutant SOD1 mouse model of ALS at different disease stages.
- Examined PGRN expression in microglia within the spinal cord.
Main Results:
- Plasma and CSF PGRN levels were not significantly different in newly diagnosed ALS patients compared to controls.
- In the mutant SOD1 mouse model, spinal cord PGRN levels increased during degeneration, correlating with enhanced microglial PGRN expression.
- CSF PGRN levels remained normal in early stages but increased with disease progression in the mouse model.
Conclusions:
- Upregulation of progranulin (PGRN) serves as a marker for the microglial response during the progression of motor neuron diseases.
- PGRN expression is dynamically regulated in response to neurodegeneration, particularly involving microglia.
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