HDL Accessory Proteins in Parkinson's Disease-Focusing on Clusterin (Apolipoprotein J) in Regard to Its Involvement in Pathology and Diagnostics-A Review

Abstract

Parkinson's disease (PD)-a neurodegenerative disorder (NDD) characterized by progressive destruction of dopaminergic neurons within the substantia nigra of the brain-is associated with the formation of Lewy bodies containing mainly α-synuclein. HDL-related proteins such as paraoxonase 1 and apolipoproteins A1, E, D, and J are implicated in NDDs, including PD. Apolipoprotein J (ApoJ, clusterin) is a ubiquitous, multifunctional protein; besides its engagement in lipid transport, it modulates a variety of other processes such as immune system functionality and cellular death signaling. Furthermore, being an extracellular chaperone, ApoJ interacts with proteins associated with NDD pathogenesis (amyloid β, tau, and α-synuclein), thus modulating their properties. In this review, the association of clusterin with PD is delineated, with respect to its putative involvement in the pathological mechanism and its application in PD prognosis/diagnosis.

Keywords: ApoA1; ApoD; ApoE; ApoJ; PON1; Parkinson’s disease; apolipoprotein J; clusterin; neurodegenerative disorders; paraoxonase.

Figure 1

Clusterin molecules can form aggregates that serve as their reservoirs. Clusterin can act as a scavenging or sequestering agent. As a scavenger agent, it can bind misfolded, toxic proteins as well as plasmin-generated protein fragments (PGPFs). The complexes between misfolded protein (or PGPFs) and clusterin are recognized by membrane receptors and trafficked inside the cell where they are degraded either by proteasomes or lysosomes. In an excess of client protein molecules, clusterin can work as a sequestering agent surrounding misfolded toxic molecules and thus preventing their toxicity. Dissociation of clusterin aggregates into heterodimeric fully active forms is enhanced when pH changes from physiological values to mildly acidic.