Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Enzyme
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Query: UMLS:C0030567 (
Parkinson's disease
)
63,064
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Recent studies indicate a causative relationship between defects in autophagy and dopaminergic neuron degeneration in
Parkinson disease
(PD). However, it is not fully understood how autophagy is regulated in the context of PD. Here we identify
USP24
(ubiquitin specific peptidase 24), a gene located in the
PARK10
(
Parkinson disease
10 [susceptibility]) locus associated with late onset PD, as a novel negative regulator of autophagy. Our data indicate that
USP24
regulates autophagy by affecting ubiquitination and stability of the ULK1 protein. Knockdown of
USP24
in cell lines and in human induced-pluripotent stem cells (iPSC) differentiated into dopaminergic neurons resulted in elevated ULK1 protein levels and increased autophagy flux in a manner independent of MTORC1 but dependent on the class III phosphatidylinositol 3-kinase (PtdIns3K) activity. Surprisingly,
USP24
knockdown also improved neurite extension and/or maintenance in aged iPSC-derived dopaminergic neurons. Furthermore, we observed elevated levels of
USP24
in the
substantia nigra
of a subpopulation of idiopathic PD patients, suggesting that
USP24
may negatively regulate autophagy in PD.
Abbreviations
: Bafilomycin/BafA: bafilomycin A
1
; DUB: deubiquitinating enzyme; iPSC: induced pluripotent stem cells; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; nt: non-targeting; PD:
Parkinson disease
; p-ATG13: phospho-ATG13; PtdIns3P: phosphatidylinositol 3-phosphate; RPS6: ribosomal protein S6; SNPs: single nucleotide polymorphisms; TH: tyrosine hydroxylase;
USP24
: ubiquitin specific peptidase 24.
...
PMID:The
PARK10
gene
USP24
is a negative regulator of autophagy and ULK1 protein stability. 3095 34
