Nemo-like kinase regulates Progranulin levels in the brain through the microglial endocytosis-lysosomal pathway

Genetic variants in Granulin (GRN), which encodes the secreted glycoprotein Progranulin (PGRN), are associated with several neurodegenerative diseases including frontotemporal lobar degeneration, neuronal ceroid lipofuscinosis, and Alzheimer's disease. These genetic alterations manifest in path...

Full description

Saved in:
Bibliographic Details
Published inbioRxiv
Main Authors Dong, Tingting, Kokubu, Hiroshi, Driessen, Terri M, Tejwani, Leon, Lim, Janghoo
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 28.06.2018
Subjects
Alzheimer's disease
Endocytosis
Frontotemporal dementia
Genetic diversity
Granulin
Microglia
Neurodegeneration
Neurodegenerative diseases
Neuronal ceroid lipofuscinosis
Pathophysiology
Phenotypes
Therapeutic applications
Online AccessGet full text

Cover

More Information
Summary:Genetic variants in Granulin (GRN), which encodes the secreted glycoprotein Progranulin (PGRN), are associated with several neurodegenerative diseases including frontotemporal lobar degeneration, neuronal ceroid lipofuscinosis, and Alzheimer's disease. These genetic alterations manifest in pathological changes due to a reduction of PGRN expression; therefore, identifying a factor that can modulate PGRN levels in vivo would enhance our understanding of PGRN in neurodegeneration, and could reveal novel potential therapeutic targets. Here, we report that Nemo-like kinase (Nlk) regulates Pgrn levels and its associated neuropathophysiology. Genetic interaction studies in mice show that Grn heterozygote mice on an Nlk heterozygote background display pathological and behavioral phenotypes which mimic Grn knockout mice. Furthermore, biochemical and cell biological studies suggest that Nlk reduction promotes Pgrn degradation via the endocytosis-lysosomal pathway, specifically in microglia. Our results reveal a new mechanism for the regulation of Pgrn in the brain and provide insight into the pathophysiology of PGRN-associated diseases.
DOI:10.1101/358010