Disruption of protein quality control in Parkinson's disease

Abstract

Parkinson's disease (PD), like a number of neurodegenerative diseases associated with aging, is characterized by the abnormal accumulation of protein in a specific subset of neurons. Although researchers have recently elucidated the genetic causes of PD, much remains unknown about what causes increased protein deposition in the disease. Given that increased protein aggregation may result not only from an increase in production, but also from decreased protein clearance, it is imperative to investigate both possibilities as potential PD culprits. This article provides a review of the systems that regulate protein clearance, including the ubiquitin proteasome system (UPS) and the autophagy-lysosomal pathway. Literature implicating failure of these mechanisms-such as UPS dysfunction resulting from environmental toxins and mutations in α-synuclein and parkin, as well as macroautophagic pathway failure because of oxidative stress and aging-in the pathogenesis of PD is also discussed.

Figure 1.

Representation of ubiquitin-proteasome proteolysis. Ubiquitin is first activated by the ubiquitin-activating enzyme E1 (A), an ubiquitin-carrier protein, E2, and ATP. The product of this reaction is a high-energy E2 ∼ ubiquitin thiol ester intermediate (B). Protein substrates are then ubiquitinated by either binding of the substrate to a specific ubiquitin-protein ligase (E3), and then the E2-bound activated ubiquitin is transferred directly to the E3-bound protein substrate. Or alternatively, the activated ubiquitin can be transferred from the E2 to the E3, prior to its conjugation to the E3-bound substrate (C). Following conjugation of the first ubiquitin molecule to the protein substrate, additional ubiquitin molecules can be added to the internal lysine residues of ubiquitin to form a polyubiquitin chain on the substrate (D). The ubiquitinated substrate is then recognized and degraded by the 26S proteasome complex, leading to the release of short peptides (E). Ubiquitin is recycled via the activity of deubiquitinating enzymes.

Figure 2.

Impact of aggregation on mechanisms of protein degradation. Soluble misfolded monomers and dimers can be recognized by both the UPS or CMA-related chaperones, and subsequently degraded by either of these two pathways. In the case of CMA, cytosolic proteins (i.e., α-synuclein) are recognized by a chaperone (i.e., Hsc70), which delivers the target protein to the lysosome via a receptor protein present in the lysosomal membrane. However, on more complex assembly (oligomer or fibril formation) of the target protein, macroautophagy is the only mechanism available to clear the more insoluble and highly ordered aggregates.