The Proteasome Inhibition Model of Parkinson’s Disease

Abstract

The pathological hallmarks of Parkinson’s disease are the progressive loss of nigral dopaminergic neurons and the formation of intracellular inclusion bodies, termed Lewy bodies, in surviving neurons. Accumulation of proteins in large insoluble cytoplasmic aggregates has been proposed to result, partly, from a failure in the function of intracellular protein degradation pathways. Evidence in support for such a hypothesis emerged in the beginning of the years 2000 with studies demonstrating structural and functional deficits in the ubiquitin-proteasome pathway in post-mortem nigral tissue of patients with Parkinson’s disease. These fundamental findings have inspired the development of a new generation of animal models based on the use of proteasome inhibitors to disturb protein homeostasis and trigger nigral dopaminergic neurodegeneration. In this review, we provide an updated overview of the current approaches in employing proteasome inhibitors to model Parkinson’s disease, with particular emphasis on rodent studies. In addition, the mechanisms underlying proteasome inhibition-induced cell death and the validity criteria (construct, face and predictive validity) of the model will be critically discussed. Due to its distinct, but highly relevant mechanism of inducing neuronal death, the proteasome inhibition model represents a useful addition to the repertoire of toxin-based models of Parkinson’s disease that might provide novel clues to unravel the complex pathogenesis of this disorder.

Nigrostriatal proteasome inhibition impairs dopamine neurotransmission and motor function in minipigs

“…Rodent models of PD have been generated using inhibitors of the UPS -a detailed review of these models can be found in Bentea et al (2017). One such inhibitor is lactacystin, which spontaneously undergoes hydrolysis to the more potent inhibitor clasto-lactacystin-β-lactone (Dick et al, 1996).…”

N-Acetyl-l-Cysteine Protects Astrocytes against Proteotoxicity without Recourse to Glutathione

“…While two previous studies determined that NAC can shield astrocytes from b-amyloid toxicity (Brera et al, 2000;de Ceballos et al, 2001), it is unknown whether NAC also protects astrocytes against the severe loss of protein quality control associated with proteasome inhibition. To address this gap, we employed the proteasome inhibitor MG132, which has been used to elicit loss of dopaminergic cells and model Parkinson's disease in vivo (Sun et al, 2006;Lu et al, 2010;Xie et al, 2010;Bentea et al, 2017). Clasto-lactacystin b-lactone and MG132 have been applied in vivo to study the role of the ubiquitin-proteasome system in a-synuclein degradation (Ebrahimi-Fakhari et al, 2011).…”

Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models

“…The proteasome system, which plays a central role in degrading dysfunctional proteins, has been shown to be impaired in the postmortem substantia nigra (SN) of PD patients (Bentea et al, 2017). Exposure to the proteasomal inhibitor carbobenzoxyl-L-leucyl-L-leucyl-L-leucine (MG-132) determined a higher susceptibility in PD patients' cells (Nguyen et al, 2011;Lin et al, 2016).…”