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Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway
Tingting Dong1, Leon Tejwani2,3, Youngseob Jung1
1Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA.
JCI Insight
|October 7, 2021
Summary
Nemo-like kinase (Nlk) in microglia regulates progranulin (PGRN) levels by affecting its degradation. Reducing Nlk enhances PGRN breakdown, impacting neurodegenerative disease pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Genetic variants in Granulin (GRN) are linked to neurodegenerative diseases.
- Reduced progranulin (PGRN) expression underlies pathological changes in these conditions.
- Understanding PGRN regulation is key for therapeutic targets.
Purpose of the Study:
- To identify factors modulating progranulin (PGRN) levels in vivo.
- To investigate the role of Nemo-like kinase (Nlk) in PGRN regulation.
- To explore the impact of Nlk on the endocytosis/lysosomal pathway in microglia.
Main Methods:
- Modulation of Nemo-like kinase (Nlk) in mouse models.
- Analysis of progranulin (PGRN) levels in the brain.
- Genetic interaction studies using Grn haploinsufficient mice.
- Investigation of the endocytosis/lysosomal pathway in microglia.
Main Results:
- Reduction of Nemo-like kinase (Nlk) in microglia alters brain progranulin (PGRN) levels.
- Nlk reduction enhances PGRN degradation via the endocytosis/lysosomal pathway in microglia.
- Nlk heterozygosity exacerbates PGRN deficiency and neuropathology in Grn haploinsufficient mice.
Conclusions:
- Nemo-like kinase (Nlk) regulates brain progranulin (PGRN) levels through microglial catabolism.
- This mechanism provides insights into PGRN-associated neurodegenerative diseases.
- Targeting Nlk in microglia may offer a novel therapeutic strategy.
