Preferred Label : Ubiquitin-Proteasomal Pathway;
NCIt related terms : Role of Parkin in the Ubiquitin-Proteasomal Pathway;
Alternative definition : BIOCARTA: The motor defects of Parkinson's disease are related to the loss of dopaminergic
neurons in specific brain regions. Examination of these neurons in diseased tissue
has revealed the presence of Lewy bodies, dense aggregates that include the protein
alpha-synuclein. A genetic basis for most cases of Parkinson's disease has not yet
been identified, but mutations in alpha-synuclein have been associated with at least
one rare form of the disease, and mutations in another protein, the parkin gene, are
associated with another inherited form of Parkinson's disease. Parkin is found in
Lewy bodies along with alpha-synuclein and the parkin protein is an E3 ubiquitin ligase.
Parkin appears to work in conjunction with ubiquitin activating (Uba)1, an E1 protein
and the ubiquitin-conjugating (Ubc) enzymes UbcH7 and 8. The E1 delivers ubiquitin
to the E2 in a cycle that creates an increasing chain of ubiquitin. The Parkin E3
ligates this onto substrates and so tags these proteins in normal cells, targeting
them for destruction in the proteasome. One of the proteins that parkin normally targets
for destruction is a specific O-glycosylated form of alpha-synuclein. Failure of parkin-mediated
degradation of alpha-synuclein may be a key factor leading to the death of dopaminergic
neurons. Another substrate of parkin is a GPCR-like protein called Pael-R that accumulates
in the ER of affected cells and may cause neuronal cell death. The involvement of
Parkin and alpha-synuclein mutations in genetic forms of Parkinson's suggests that
failure of ubiquitination and protein degradation may be causative in other forms
of Parkinson's. Questions remaining include the cause of the lack of effective ubiquitination
in individuals lacking obvious genetic defects in this pathway and how to use this
knowledge of ubiquitination and protein degradation in Parkinson's disease to identify
therapeutic strategies. (This definition may be outdated - see the DesignNote.);
NCIt note : The BIOCARTA Definition (ALT_DEFINITION) for this pathway concept was provided by
BioCarta. This property was not created by, nor is it maintained by the NCI Thesaurus
staff. Additionally, BioCarta is no longer updating its pathway data; thus, the BIOCARTA
Definition might be outdated or inaccurate. Please see the Terms and Conditions for
Use at http://www.biocarta.com/.;
Biocarta ID : h_parkinPathway;
Origin ID : C39182;
UMLS CUI : C1519748;
Semantic type(s)
- has_gene_product_element
- pathway_has_gene_element
