Cellular processing of proteins involved in the pathogenesis of Parkinson disease

Model of dopaminergic cell death and possible sites for therapeutic intervention in PD. Studies on inherited forms of PD have led to the identification of genes that, when mutated, lead to dopaminergic cell loss. These genes are involved in a variety of cellular processes that include protein ubiquitination and degradation via the proteasome, response to oxidative stress, protein phosphorylation, mitochondrial function, and protein folding. Potential points of therapeutic intervention are highlighted: gene silencing therapies to reduce synuclein levels (i); inhibitors of synuclein aggregation and/or processing (ii); interventions to downregulate toxic substrates or upregulate parkin or proteasomal function (iii); interventions to enhance mitochondrial function with factors such as CoQ10, DJ-1, or PINK-1 (iv); free radical scavengers and antioxidants (v); kinase inhibitors to block LRRK2 activity or interventions to increase PINK-1 function (vi); and other therapies using trophic factors such as GDNF, survival genes, or fetal/stem cell replacement that would protect or replace susceptible cells (vii).