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Cited by 13Neuroinflammation and Neurodegeneration MechanismsLysosomal Storage Disorders ResearchCellular transport and secretion

Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway

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Dong, Tingting, Tejwani, Leon, Jung, Youngseob, Kokubu, Hiroshi, Luttik, Kimberly, Driessen, Terri M., Lim, Janghoo·2021·JCI Insight
DOI 10.1172/jci.insight.136147PMC PMC8663778
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Abstract

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 factors 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 modulation of the endocytosis/lysosomal pathway via reduction of Nemo-like kinase (Nlk) in microglia, but not in neurons, can alter total brain Pgrn levels in mice. We demonstrate that Nlk reduction promotes Pgrn degradation by enhancing its trafficking through the endocytosis/lysosomal pathway, specifically in microglia. Furthermore, genetic interaction studies in mice showed that Nlk heterozygosity in Grn haploinsufficient mice further reduces Pgrn levels and induces neuropathological phenotypes associated with PGRN deficiency. Our results reveal a mechanism for Pgrn level regulation in the brain through the active catabolism by microglia and provide insights into the pathophysiology of PGRN-associated diseases.

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  • Mice with partial genetic reduction of Nlk display no pathological (neurodegenerative or inflammatory), survival, or cognitive changes up to 52 weeks.

    “mice with partial genetic reduction of Nlk display no pathological (neurodegenerative or inflammatory), survival, or cognitive changes up to 52 weeks (57)”

    From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [57]

    The Results sections report no significant microglial changes or elevated-plus-maze behavioral phenotype in Nlk+/– mice alone at one year, compared with wild-type controls. They do not establish unchanged survival or explicitly report normal cognitive performance for Nlk+/– mice alone; the reported Morris water maze impairment concerns Nlk+/– Grn+/– mice. Thus, the claim is broader than the findings in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Mice with postnatal whole-body conditional ablation of Nlk are grossly normal.

    “and mice with postnatal whole-body conditional ablation of Nlk are grossly normal (57)”

    From Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration (2023) · cites this paper as [57]

    The Results (‘Decreased expression of Nlk reduces Pgrn levels in vivo’; page unavailable) describe tamoxifen-induced conditional deletion of Nlk in all cell types beginning at six weeks of age. They report reduced cortical Nlk and Pgrn levels, but do not say that these mice were grossly normal. The normal behavioral findings elsewhere in the Results concern Nlk heterozygotes, not the conditionally ablated mice. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Dong, T., Tejwani, L., Jung, Y., Kokubu, H., Luttik, K., Driessen, T. M., & Lim, J.
Affiliations
Yale University (US)
Corresponding author
Lim, Janghoo
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2021-11-22
Volume
6
Issue
22
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.136147
PMC
PMC8663778
OpenAlex
W3203993850
Cited by
13
References
8
Citations by year
2026: 5 · 2025: 1 · 2023: 4 · 2022: 3
FWCI
0.70
Type
journal article
Language
en
Open access
Licence
Locations
  • JCI Insight (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Neurological Disorders and Stroke (NS083706, NS088321, NS007224)
  • National Institute of Mental Health (MH119803)
  • Lo Family Fellowship for Excellence in Stem Cell Research (N/A)
  • National institutes on aging (AG066447)
  • National Institute on Aging (AG074609)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
progranulin, microglia, Nemo-like kinase, endocytosis, lysosomal degradation, frontotemporal lobar degeneration, neuronal ceroid lipofuscinosis, Alzheimer's disease, neurodegeneration
MeSH terms
Progranulins, Animals, Disease Models, Animal, Endocytosis, Humans, Lysosomes, Microglia, Mice

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