Microglia regulate brain progranulin levels through the 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 patholog...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2021-11-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.136147 |
| _version_ | 1811334885519917056 |
|---|---|
| author | Tingting Dong Leon Tejwani Youngseob Jung Hiroshi Kokubu Kimberly Luttik Terri M. Driessen Janghoo Lim |
| author_facet | Tingting Dong Leon Tejwani Youngseob Jung Hiroshi Kokubu Kimberly Luttik Terri M. Driessen Janghoo Lim |
| author_sort | Tingting Dong |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T17:14:42Z |
| format | Article |
| id | doaj.art-83878021b4ae453a89af51ee5d8cbe4b |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-04-13T17:14:42Z |
| publishDate | 2021-11-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-83878021b4ae453a89af51ee5d8cbe4b2022-12-22T02:38:09ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-11-01622Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathwayTingting DongLeon TejwaniYoungseob JungHiroshi KokubuKimberly LuttikTerri M. DriessenJanghoo LimGenetic 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.https://doi.org/10.1172/jci.insight.136147Neuroscience |
| spellingShingle | Tingting Dong Leon Tejwani Youngseob Jung Hiroshi Kokubu Kimberly Luttik Terri M. Driessen Janghoo Lim Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway JCI Insight Neuroscience |
| title | Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway |
| title_full | Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway |
| title_fullStr | Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway |
| title_full_unstemmed | Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway |
| title_short | Microglia regulate brain progranulin levels through the endocytosis/lysosomal pathway |
| title_sort | microglia regulate brain progranulin levels through the endocytosis lysosomal pathway |
| topic | Neuroscience |
| url | https://doi.org/10.1172/jci.insight.136147 |
| work_keys_str_mv | AT tingtingdong microgliaregulatebrainprogranulinlevelsthroughtheendocytosislysosomalpathway AT leontejwani microgliaregulatebrainprogranulinlevelsthroughtheendocytosislysosomalpathway AT youngseobjung microgliaregulatebrainprogranulinlevelsthroughtheendocytosislysosomalpathway AT hiroshikokubu microgliaregulatebrainprogranulinlevelsthroughtheendocytosislysosomalpathway AT kimberlyluttik microgliaregulatebrainprogranulinlevelsthroughtheendocytosislysosomalpathway AT terrimdriessen microgliaregulatebrainprogranulinlevelsthroughtheendocytosislysosomalpathway AT janghoolim microgliaregulatebrainprogranulinlevelsthroughtheendocytosislysosomalpathway |