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 a-synuclein and parkin, as well as macroautophagic pathway failure because of oxidative stress and aging-in the pathogenesis of PD is also discussed.

HMGB1 is involved in autophagy inhibition caused by SNCA/α-synuclein overexpression

“…However, for the more insoluble oligomeric and aggregated SNCA, macroautophagy is the only mechanism for their clearance. 4,5 The initiation of macroautophagy (here referred to as autophagy) is regulated by multiple signaling pathways involving 2 macromolecular complexes: the MTOR -ULK1-ATG13-RB1CC1-C12orf44/ATG101 complex (the latter gene product, C12orf44, is also known as RGD1359310 in the rat and 9430023L20Rik in mice), and the BECN1-PIK3C3 (ortholog of yeast Vps34) complex. 6 BECN1 plays an essential role in autophagy initiation by interacting with various cofactors, 7 one of which is high mobility group box 1.…”

Emerging role of autophagy in pediatric neurodegenerative and neurometabolic diseases

“…Crosstalk is of outmost importance for neurodegenerative diseases where a primary failure of degradation mechanisms has been proposed. [1][2][3][14][15][16] Dysfunction of autophagy can result from a block at every level of the pathway (Figure 2). With regards to neuronal pathology, defects in the autophagy pathway can be divided into those that cause impaired autophagic turnover and those that result in deregulated and overactive autophagy.…”

Proteasomal Inhibition as a Treatment Strategy for Parkinson's Disease: The Impact of α-Synuclein on Nurr1

“…Moreover, disruption of this system has been proposed to contribute to several neurodegenerative diseases, including PD. Although Lin et al (2012) observed no clear change in proteasomal function in untreated A53T mice, function was impaired in previous PD models in which ␣-synuclein was mutated or overexpressed (Cook et al, 2012). Furthermore, genetic ablation of the 26S proteasome complex in transgenic mice, which completely abolishes ubiquitinmediated proteasomal degradation, causes neurodegeneration and intraneuronal ␣-synuclein pathology resembling human Lewy bodies (Bedford et al, 2008).…”