PMID:26911690

Citation	Song, P, Trajkovic, K, Tsunemi, T and Krainc, D (2016) Parkin Modulates Endosomal Organization and Function of the Endo-Lysosomal Pathway. J. Neurosci. 36:2425-37
Abstract	Mutations in PARK2 (parkin), which encodes Parkin protein, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson's disease (PD). While several studies implicated Parkin in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration upon Parkin loss of function remains incompletely understood. In this study, we found that Parkin modulates the endocytic pathway through the regulation of endosomal structure and function. We showed that loss of Parkin function led to decreased endosomal tubulation and membrane association of vesicle protein sorting 35 (VPS35) and sorting nexin 1 (SNX1), as well as decreased mannose 6 phosphate receptor (M6PR), suggesting the impairment of retromer pathway in Parkin-deficient cells. We also found increased formation of intraluminal vesicles coupled with enhanced release of exosomes in the presence of mutant Parkin. To elucidate the molecular mechanism of these alterations in the endocytic pathway in Parkin-deficient cells, we found that Parkin regulates the levels and activity of Rab7 by promoting its ubiquitination on lysine 38 residue. Both endogenous Rab7 in Parkin-deficient cells and overexpressed K38 R-Rab7 mutant displayed decreased effector binding and membrane association. Furthermore, overexpression of K38R-Rab7 in HEK293 cells phenocopied the increased secretion of exosomes observed in Parkin-deficient cells, suggesting that Rab7 deregulation may be at least partially responsible for the endocytic phenotype observed in Parkin-deficient cells. These findings establish a role for Parkin in regulating the endo-lysosomal pathway and retromer function and raise the possibility that alterations in these pathways contribute to the development of pathology in Parkin-linked Parkinson's disease.
Links	PubMed Online version:10.1523/JNEUROSCI.2569-15.2016
Keywords	Adult; Cells, Cultured; Endosomes/metabolism; Female; HEK293 Cells; Humans; Induced Pluripotent Stem Cells/metabolism; Lysosomes/metabolism; Male; Signal Transduction/physiology; Ubiquitin-Protein Ligases/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:PRKN	involved_in	GO:1905281: positive regulation of retrograde transport, endosome to Golgi	ECO:0000303: author statement without traceable support used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PRKN	involved_in	GO:1905477: positive regulation of protein localization to membrane	ECO:0000305: curator inference used in manual assertion	GO:0016567	P	has_input:(UniProtKB:P51149)	Seeded From UniProt	complete
HUMAN:PRKN	involved_in	GO:1903542: negative regulation of exosomal secretion	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PRKN	involved_in	GO:0016567: protein ubiquitination	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:P51149) positively_regulates:(GO:0005515) positively_regulates:(GO:0072657)|occurs_in(CL:0000700) has_input:(UniProtKB:P51149)	Seeded From UniProt	complete
HUMAN:PRKN	involved_in	GO:0031647: regulation of protein stability	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:P51149)	Seeded From UniProt	complete
HUMAN:PRKN	involved_in	GO:0032092: positive regulation of protein binding	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:Q96NA2) has_input:(UniProtKB:P51149)	Seeded From UniProt	complete
HUMAN:PRKN	involved_in	GO:1905366: negative regulation of intralumenal vesicle formation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PRKN	involved_in	GO:1905477: positive regulation of protein localization to membrane	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_input:(UniProtKB:Q96QK1)|has_input:(UniProtKB:Q13596)	Seeded From UniProt	complete
HUMAN:RAB7A	located_in	GO:0010008: endosome membrane	ECO:0000315: mutant phenotype evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:RAB7A	enables	GO:0005515: protein binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:Q96NA2	F		Seeded From UniProt	complete
HUMAN:PRKN2	involved_in	GO:1905281: positive regulation of retrograde transport, endosome to Golgi	ECO:0000303: author statement without traceable support used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PRKN2	involved_in	GO:0016567: protein ubiquitination	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_direct_input:(UniProtKB:P51149) positively_regulates:(GO:0005515) positively_regulates:(GO:0072657)|occurs_in(CL:0000700) has_direct_input:(UniProtKB:P51149)	Seeded From UniProt	complete
HUMAN:PRKN2	involved_in	GO:1905366: negative regulation of intralumenal vesicle formation	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PRKN2	involved_in	GO:1905477: positive regulation of protein localization to membrane	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_regulation_target:(UniProtKB:Q96QK1)|has_regulation_target:(UniProtKB:Q13596)	Seeded From UniProt	complete
HUMAN:PRKN2	involved_in	GO:1905477: positive regulation of protein localization to membrane	ECO:0000305: curator inference used in manual assertion	GO:0016567	P	has_regulation_target:(UniProtKB:P51149)	Seeded From UniProt	complete
HUMAN:PRKN2	involved_in	GO:0031647: regulation of protein stability	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_regulation_target:(UniProtKB:P51149)	Seeded From UniProt	complete
HUMAN:PRKN2	involved_in	GO:1903542: negative regulation of exosomal secretion	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:PRKN2	involved_in	GO:0032092: positive regulation of protein binding	ECO:0000315: mutant phenotype evidence used in manual assertion		P	has_regulation_target:(UniProtKB:Q96NA2) has_regulation_target:(UniProtKB:P51149)	Seeded From UniProt	complete
HUMAN:RILP	enables	GO:0031267: small GTPase binding	ECO:0000353: physical interaction evidence used in manual assertion	UniProtKB:P51149	F		Seeded From UniProt	complete
HUMAN:RAB7A	part_of	GO:0010008: endosome membrane	ECO:0000315: mutant phenotype evidence used in manual assertion		C		Seeded From UniProt	complete
HUMAN:RAB7A	involved_in	GO:1903542: negative regulation of exosomal secretion	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:RAB7A	involved_in	GO:1905366: negative regulation of intralumenal vesicle formation	ECO:0000304: author statement supported by traceable reference used in manual assertion		P		Seeded From UniProt	complete

References

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