E-resources
Peer reviewed
Open access
-
Logan, Todd; Simon, Matthew J.; Rana, Anil; Cherf, Gerald M.; Srivastava, Ankita; Davis, Sonnet S.; Low, Ray Lieh Yoon; Chiu, Chi-Lu; Fang, Meng; Huang, Fen; Bhalla, Akhil; Llapashtica, Ceyda; Prorok, Rachel; Pizzo, Michelle E.; Calvert, Meredith E.K.; Sun, Elizabeth W.; Hsiao-Nakamoto, Jennifer; Rajendra, Yashas; Lexa, Katrina W.; Srivastava, Devendra B.; van Lengerich, Bettina; Wang, Junhua; Robles-Colmenares, Yaneth; Kim, Do Jin; Duque, Joseph; Lenser, Melina; Earr, Timothy K.; Nguyen, Hoang; Chau, Roni; Tsogtbaatar, Buyankhishig; Ravi, Ritesh; Skuja, Lukas L.; Solanoy, Hilda; Rosen, Howard J.; Boeve, Bradley F.; Boxer, Adam L.; Heuer, Hilary W.; Dennis, Mark S.; Kariolis, Mihalis S.; Monroe, Kathryn M.; Przybyla, Laralynne; Sanchez, Pascal E.; Meisner, Rene; Diaz, Dolores; Henne, Kirk R.; Watts, Ryan J.; Henry, Anastasia G.; Gunasekaran, Kannan; Astarita, Giuseppe; Suh, Jung H.; Lewcock, Joseph W.; DeVos, Sarah L.; Di Paolo, Gilbert
Cell, 09/2021, Volume: 184, Issue: 18Journal Article
GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn–/– mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn–/– brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN—a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn–/– phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn–/– CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD. Display omitted •Grn–/– mice exhibit robust BMP lipid deficiency with concurrent GlcSph accumulation•BMP stimulates glucocerebrosidase activity and lysosome function in Grn–/– models•PGRN was fused to a human transferrin receptor binding Fc to increase CNS exposure•PTV:PGRN biologic rescues Grn–/– CNS lysosomal, microglial, and neuronal dysfunction Peripherally delivered progranulin biologic with enhanced CNS biodistribution corrects CNS disease pathology of the GRN mouse model of frontotemporal dementia.
Author
![loading ... loading ...](themes/default/img/ajax-loading.gif)
Shelf entry
Permalink
- URL:
Impact factor
Access to the JCR database is permitted only to users from Slovenia. Your current IP address is not on the list of IP addresses with access permission, and authentication with the relevant AAI accout is required.
Year | Impact factor | Edition | Category | Classification | ||||
---|---|---|---|---|---|---|---|---|
JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
Select the library membership card:
If the library membership card is not in the list,
add a new one.
DRS, in which the journal is indexed
Database name | Field | Year |
---|
Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
---|
Source: Personal bibliographies
and: SICRIS
The material is available in full text. If you wish to order the material anyway, click the Continue button.