Function

 Parkin is important for aggresome formation in human neuronal cells.

Pathology

Parkin is found in Lewy bodies along with alpha-synuclein. The parkin protein is an E3 ubiquitin ligase.

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.

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 suggest that failure of ubiquitination and protein degradation may be causative in other forms of Parkinson disease.