Targeting Protein Degradation Pathways

Accumulation of misfolded proteins contributes to aggregation, and one current method aimed at reducing or eliminating alpha-synuclein aggregation targets cellular pathways of protein degradation (the ubiquitin-proteosome pathway (UBP) and the lysosomal degradation pathway), and identifying and manipulating dysfunction in these pathways. As an E3 ubiquitin ligase, Parkin is an attractive target to modulate protein degradation via the UBP. Accumulation of known Parkin substrates (Pael-1, Hsp-70, CDCrel-1, glycosylated alpha-synuclein, and synphillin-1) is implicated in PD pathology (Yang et al., 2009; Cookson, 2005).

Active areas of investigation include identifying compounds that can modulate Parkin activity and using viral vectors to express Parkin as a therapeutic strategy.