Protein Degradation Pathways

A number of genetic factors associated with Parkinson’s disease involve protein degradation and the UBP pathway in particular (including parkin, DJ-1, and UCHL1). Protein aggregation is a hallmark feature of PD: Lewy bodies composed of misfolded proteins and ubiquitin are a defining clinical characteristic. Though it is unclear whether aggregation is protective or pathogenic, the underlying cause appears to be dysfunction in the normal pathways of protein degradation: the lysosomal degradation pathway and the ubiquitin-proteosome pathway.

Lysosomes are organelles that contain digestive enzymes surrounded by membrane used to digest and degrade the contents of vacuoles. Lysosomal degradation is utilized during phagocytosis, endocytosis and autophagy to digest proteins. Lysosomal degradation may also be employed to breakdown misfolded or aggregated proteins in PD.

The UBP pathway is the major mechanism used to degrade abnormal proteins, or proteins at the ends of their life cycles. Proteins that are targeted for degradation are covalently modified with ubiquitin on lysine residues. This modification requires three enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). Whereas E1 and E2 enzymes are few in number and function mostly non-specifically, E3 enzymes are numerous and highly specific for a limited number of substrates, controlling which proteins are targeted for degradation. These enzymes attach Lysine48-linked poly-ubiquitin chains which direct proteins to the proteasome for degradation.

Parkin (PARK2), an E3 ubiquitin ligase, is the second most common target of genetic mutation leading to Parkinson's disease.