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PMID:26911690

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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

Significance

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

Notes

See also

References

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