Tuesday 16 December 2003
Parkin appears to work in conjuction with ubiquitin activating (Uba)1, an E1 protein and the ubiquitin-conjugating (Ubc) enzymes UbcH7&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 proteosome.
One of the proteins that parkin normally targets for destruction is a specific O-glycosylated form of alpha-synuclein.
Parkin substrates: p38, CDCRel-1, Synucléine, SytXI, Synphiline, Pael-R, Tubuline, Cycline E, DAT, FBP1, RanBP2.
Parkin is found in Lewy bodies along with alpha-synuclein.
Failure of parkin-mediated degradation of alpha-synuclein (SNCA) 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 suggest that failure of ubiquitination and protein degradation may be causative in other forms of Parkinson disease.
8 mutated Parkinson genes known (2008)
Open access references
Association study of major risk single nucleotide polymorphisms in the common regulatory region of PARK2 and PACRG genes with leprosy in an Indian population. Malhotra D, Darvishi K, Lohra M, Kumar H, Grover C, Sood S, Reddy BS, Bamezai RN. Eur J Hum Genet. 2006 Apr;14(4):438-42. PMID: 16391553 (Free)
Susceptibility to leprosy is associated with PARK2 and PACRG. Mira MT, Alcaïs A, Nguyen VT, Moraes MO, Di Flumeri C, Vu HT, Mai CP, Nguyen TH, Nguyen NB, Pham XK, Sarno EN, Alter A, Montpetit A, Moraes ME, Moraes JR, Doré C, Gallant CJ, Lepage P, Verner A, Van De Vosse E, Hudson TJ, Abel L, Schurr E. Nature. 2004 Feb 12;427(6975):636-40. Epub 2004 Jan 25. PMID: 14737177 (Free)
HtrA2 and Parkinson’s disease: think PINK? Emad S. Alnemri. Nature Cell Biology 9, 1227 - 1229 (2007)
Mata IF, Lockhart PJ, Farrer MJ. Parkin genetics: one model for Parkinson’s disease. Hum Mol Genet. 2004 Apr 1;13 Spec No 1:R127-33. PMID: 14976155