Parkin, Ubiquitination and Cell Death

Project: Research project

Project Details


DESCRIPTION (Provided by Applicant): Parkinson's disease (PD) is a major public
health problem in North America. Although PD has been regarded as having only a
minor heritable component, recent discoveries have highlighted the contribution
of genetics to this disease, with the description of dominant and recessive
inherited forms of PD in several families. A wide variety of mutations in the
parkin gene are associated with autosomal recessive forms of PD, especially
"juvenile" onset forms where symptoms start before the fourth decade of life.
Inheritance of certain parkin mutations result in greatly reduced parkin
protein expression. The function of the parkin protein is unknown but recent
results strongly suggest that it is a ubiquitin-protein ligase, or at least a
component of a multi subunit ligase. Ubiquitination is a major way in which
cells dispose of misfolded or damaged proteins, as well as a way in which the
cell regulates levels of specific proteins. A point mutation in a second gene
that may affect ubiquitination, UCH-L1, has been reported to be associated with
autosomal dominant familial PD. The major pathological hallmark of PD is loss
of dopamine containing cells in the substantia nigra (SN). How loss of parkin
function causes damage to dopaminergic cells is not yet known, but a prediction
of the hypothesis that parkin is an ubiquitin-protein ligase is that parkin is
involved in the removal of misfolded and/or potentially toxic proteins from
cells. We hypothesize that lack of parkin expression in dopaminergic cells of
the SN causes an accumulation of an unidentified protein or set of proteins
(protein x) which is/are toxic. The effects of UCH-L1 mutations may be similar,
in that these would be predicted to also affect ubiquitination and hence
increase the concentration of toxic protein(s) within the cell. The studies in
this proposal aim to test this hypothesis in cellular systems which have been
carefully chosen to be relevant to dopaminergic cells. Specifically we will
perform functional studies of the potential role of parkin and UCH-L1 protein
in ubiquitination. We will attempt to understand how mutations in parkin result
in altered function of this protein and how it is regulated within the cell. We
will also look at the effects of loss of parkin function on cell death and on
ubiquitination reactions within the cell. We will also attempt to address the
idea that mutations in parkin and UCH-L1 may interact in the same pathway, and
examine the balance between use of ubiquitin by reactions catalyzed by parkin,
and the production of free ubiquitin via UCH-L1.
Effective start/end date7/15/016/30/06


  • Medicine(all)
  • Neuroscience(all)