Proteotoxicity

About: Proteotoxicity is a research topic. Over the lifetime, 549 publications have been published within this topic receiving 23151 citations.

Astrocyte plasticity revealed by adaptations to severe proteotoxic stress

Abstract: Neurodegeneration is characterized by an accumulation of misfolded proteins in neurons. It is less well appreciated that glia often also accumulate misfolded proteins. However, glia are highly plastic and may adapt to stress readily. Endogenous adaptations to stress can be measured by challenging stressed cells with a second hit and then measuring viability. For example, subtoxic stress can elicit preconditioning or tolerance against second hits. However, it is not known if severe stress that kills half the population can elicit endogenous adaptations in the remaining survivors. Glia, with their resilient nature, offer an ideal model in which to test this new hypothesis. The present study is the first demonstration that astrocytes surviving one LC50 hit of the proteasome inhibitor MG132 were protected against a second MG132 hit. ATP loss in response to the second hit was also prevented. MG132 caused compensatory rises in stress-sensitive heat shock proteins. However, stressed astrocytes exhibited an even greater rise in ubiquitin-conjugated proteins upon the second hit, illustrating the severity of the proteotoxicity and verifying the continued impact of MG132. Despite this stress, MG132-pretreated astrocytes were completely prevented from losing glutathione with the second hit. Furthermore, inhibiting glutathione synthesis rendered astrocytes sensitive to the second hit, unmasking the cumulative impact of two hits by removal of an endogenous adaptation. These findings suggest that stressed astrocytes become progressively harder to kill by virtue of antioxidant defenses. Such plasticity may permit astrocytes under severe stress to better support neurons and help explain the protracted nature of neurodegeneration.

Inhibition of Cytohesins Protects against Genetic Models of Motor Neuron Disease

Abstract: Mutant genes that underlie Mendelian forms of amyotrophic lateral sclerosis (ALS) and biochemical investigations of genetic disease models point to potential driver pathophysiological events involving endoplasmic reticulum (ER) stress and autophagy. Several steps in these cell biological processes are known to be controlled physiologically by small ADP-ribosylation factor (ARF) signaling. Here, we investigated the role of ARF guanine nucleotide exchange factors (GEFs), cytohesins, in models of ALS. Genetic or pharmacological inhibition of cytohesins protects motor neurons in vitro from proteotoxic insults and rescues locomotor defects in a Caenorhabditis elegans model of disease. Cytohesins form a complex with mutant superoxide dismutase 1 (SOD1), a known cause of familial ALS, but this is not associated with a change in GEF activity or ARF activation. ER stress evoked by mutant SOD1 expression is alleviated by antagonism of cytohesin activity. In the setting of mutant SOD1 toxicity, inhibition of cytohesin activity enhances autophagic flux and reduces the burden of misfolded SOD1. These observations suggest that targeting cytohesins may have potential benefits for the treatment of ALS.

Transmission of proteotoxicity across cellular compartments

Abstract: An important subgroup of human neurodegenerative diseases is associated with abnormal expansions of glutamine repeats found in several otherwise unrelated proteins (Zoghbi and Orr 2000). Interest in these polyglutamine diseases is fueled both by their clinical significance and by the belief that lessons gleaned from these relatively rare conditions will apply to other more prevalent human neurodegenerative disorders and perhaps more generally to other diseases of aging. The basis for this belief is the observation that polyglutamine diseases and common neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, share as a common feature the accumulation of abnormal protein aggregates in and around affected neurons (Kaytor and Warren 1999). In the polyglutamine diseases there is a good correlation between the length of the glutamine repeat, the tendency of the affected protein to assume abnormal aggregation-prone states of folding, and the occurrence of neurodegeneration (Gusella and MacDonald 2000; Orr 2001). Furthermore, there is reason to believe that despite the dissimilarities in structure and function of the proteins that “host” the glutamine repeat, once the polyglutamine expansion has reached a critical length, it imposes a common abnormal folding state on the affected protein (Perutz 1996). Together with the dominant inheritance pattern of the associated diseases, these observations suggest that the abnormal polyglutamine repeat converts host proteins into toxic entities, or proteotoxins (Hightower 1991). Attempts to understand the pathophysiology of polyglutamine diseases have therefore focused on the physical state of the abnormal protein, the cellular compartment in which it is found, and the impact of the abnormal protein on cell physiology. A paper in this issue of Genes & Development reports on a pathogenic polyglutamine protein that accumulates as a nuclear aggregate yet triggers the unfolded protein response—a cellular response to unfolded and misfolded proteins in the endoplasmic reticulum (Nishitoh et al. 2002). We will discuss some of the implications of this finding whereby the impact of a polyglutamine-containing proteotoxin can be transmitted from one cellular compartment to another.