Dysfunction of Cellular Proteostasis in Parkinson's Disease

Abstract

Despite decades of research, current therapeutic interventions for Parkinson's disease (PD) are insufficient as they fail to modify disease progression by ameliorating the underlying pathology. Cellular proteostasis (protein homeostasis) is an essential factor in maintaining a persistent environment for neuronal activity. Proteostasis is ensured by mechanisms including regulation of protein translation, chaperone-assisted protein folding and protein degradation pathways. It is generally accepted that deficits in proteostasis are linked to various neurodegenerative diseases including PD. While the proteasome fails to degrade large protein aggregates, particularly alpha-synuclein (α-SYN) in PD, drug-induced activation of autophagy can efficiently remove aggregates and prevent degeneration of dopaminergic (DA) neurons. Therefore, maintenance of these mechanisms is essential to preserve all cellular functions relying on a correctly folded proteome. The correlations between endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) that aims to restore proteostasis within the secretory pathway are well-established. However, while mild insults increase the activity of chaperones, prolonged cell stress, or insufficient adaptive response causes cell death. Modulating the activity of molecular chaperones, such as protein disulfide isomerase which assists refolding and contributes to the removal of unfolded proteins, and their associated pathways may offer a new approach for disease-modifying treatment. Here, we summarize some of the key concepts and emerging ideas on the relation of protein aggregation and imbalanced proteostasis with an emphasis on PD as our area of main expertise. Furthermore, we discuss recent insights into the strategies for reducing the toxic effects of protein unfolding in PD by targeting the ER UPR pathway.

Keywords: ER stress; UPR; alpha-synuclein; protein disulfide isomerase; proteostasis; refolding.

FIGURE 1

Major pathways of alpha-synuclein clearance in PD. (A) In the ubiquitin-proteosome pathway, mα-SYN is tagged with ubiquitin molecules and transferred to the proteosome complex for ATP dependant degradation. (B) In the autophagy-lysosomal pathway (ALP), three different pathways have been described: microautophagy (microAφ), macroautophagy (macroAφ) and chaperone-mediated autophagy (CMA). While evidence linking microAφ and mα-SYN is still missing, in macroAφ, mα-SYN is sequestered by a double membrane-organelles called autophagosomes before fusion with lysosome. In CMA, mα-SYN bind to protein chaperones, which help to target them directly to the lysosome for enzymatic degradation.

FIGURE 2

Unfolded protein response (UPR) in response to alpha-synuclein misfolding. Three transmembrane proteins have been identified as sensors of unfolded proteins in the ER in mammalian cells: IRE1 (inositol-requiring protein 1), ATF6 (activating transcription factor 6), and PERK (protein kinase RNA-like ER kinase). Upon the accumulation of mα-SYN, BiP dissociates from UPR sensors inducing their activation that leads to the transcription of genes whose protein products increase the folding capacity of the cell.

FIGURE 3

Excessive protein refolding in ER leads to oxidative stress and apoptosis. Depending on the structure, aggregates can be degraded either by macroautophagy or CMA. Alternatively, misfolded α-SYN undergoes refolding in the ER. However, excessive refolding upregulates PDI reduction. Re-oxidation of PDI is linked with an increase in hydrogen peroxide generation causing dysregulation of IP3R permeability and an increase in cytosolic calcium. Calcium release from the ER may activate calpain and eventually lead to apoptosis. The pharmacological inhibition of PDI by bacitracin or cystamine prevents ER redox imbalance and downstream proapoptotic events. The inhibition of the ERO1 catalyzed re-oxidation of PDI by EN460 results in a protective effect similar to PDI inhibitor.