Parkin
is involved in protein degradation as a ubiquitin-protein
ligase. The PARK2 gene is mutant in autosomal recessive
juvenile parkinsonism.
Parkinson’s Disease, the second
most common neurodegenerative disease after Alzheimer’s
Disease, is characterized by the loss of dopaminergic
neurons and the presence of
Lewy bodies (comprised of alpha-synuclein and parkin
inclusions). Autosomal Recessive Juvenile Parkinsonism
(AR-JP) is a
recently described form of Parkinson?s Disease that
has been linked to a gene that codes for parkin. Parkin,
a
52 kDa protein, has a suggested role in the ubiquitin/proteasome
pathway for protein degradation. The amino terminus
bears sequence homology to ubiquitin while functionally
it acts
as a RING-type ubiquitin protein ligase (E3) that coordinates
the transfer of ubiquitin to substrate proteins, thus
targeting them for degradation by the proteasome.
Studies
show that parkin interacts with and ubiquitinates
the alpha-synuclein interacting protein, synphilin-1.
Recent analysis of parkin mutations in AR-JP patients
reveals
that parkin becomes functionally inactive as an E3
enzyme. This suggests that the loss of function mutation
within
parkin results in a failure of ubiquitin/proteasome-mediated
proteolysis of synphilin-1 and the accumulation of
proteins within the cell resulting in neuronal cell
death. |
