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Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations.
- Source :
-
Cells [Cells] 2020 Jul 17; Vol. 9 (7). Date of Electronic Publication: 2020 Jul 17. - Publication Year :
- 2020
-
Abstract
- Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) cause familial Parkinson's disease, and sequence variations are associated with the sporadic form of the disease. LRRK2 phosphorylates a subset of RAB proteins implicated in secretory and recycling trafficking pathways, including RAB8A and RAB10. Another RAB protein, RAB29, has been reported to recruit LRRK2 to the Golgi, where it stimulates its kinase activity. Our previous studies revealed that G2019S LRRK2 expression or knockdown of RAB8A deregulate epidermal growth factor receptor (EGFR) trafficking, with a concomitant accumulation of the receptor in a RAB4-positive recycling compartment. Here, we show that the G2019S LRRK2-mediated EGFR deficits are mimicked by knockdown of RAB10 and rescued by expression of active RAB10. By contrast, RAB29 knockdown is without effect, but expression of RAB29 also rescues the pathogenic LRRK2-mediated trafficking deficits independently of Golgi integrity. Our data suggest that G2019S LRRK2 deregulates endolysosomal trafficking by impairing the function of RAB8A and RAB10, while RAB29 positively modulates non-Golgi-related trafficking events impaired by pathogenic LRRK2.
- Subjects :
- Epidermal Growth Factor metabolism
Gene Knockdown Techniques
Golgi Apparatus metabolism
HeLa Cells
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics
Mutation genetics
Protein Transport
Proteolysis
rab4 GTP-Binding Proteins metabolism
rab7 GTP-Binding Proteins
Endosomes metabolism
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 metabolism
Lysosomes metabolism
rab GTP-Binding Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2073-4409
- Volume :
- 9
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cells
- Publication Type :
- Academic Journal
- Accession number :
- 32709066
- Full Text :
- https://doi.org/10.3390/cells9071719