Glucose Regulated Protein 78 Diminishes α-Synuclein Neurotoxicity in a Rat Model of Parkinson Disease

Gorbatyuk, Marina S.; Shabashvili, Arseniy E.; Chen, Weijun; Meyers, Craig; Sullivan, Layla F; Salganik, Max; Lin, Jonathan H.; Lewin, Alfred S.; Muzyczka, Nicholas; Gorbatyuk, Oleg S.

doi:10.1038/mt.2012.28

Cited by 157 publications

(144 citation statements)

References 48 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…On the other hand, mutations in HSPA9 are not common in earlyonset Parkinson's disease (Freimann et al 2013). The endoplasmic reticulum Hsp70 family member, GRP78, has been shown to reduce α-synuclein toxicity in experimental models of Parkinson's disease (Gorbatyuk et al 2012). However, polymorphisms in the gene coding for GRP78 (HSPA5) are not thought to be strongly associated with an increased risk for developing the disorder (Chen et al 2008).…”

Section: Heat Shock Proteins In Neurodegenerative Disorders and Agingmentioning

confidence: 99%

Heat shock proteins in neurodegenerative disorders and aging

Leak

2014

J. Cell Commun. Signal.

143

119

View full text Add to dashboard Cite

Many members of the heat shock protein family act in unison to refold or degrade misfolded proteins. Some heat shock proteins also directly interfere with apoptosis. These homeostatic functions are especially important in proteinopathic neurodegenerative diseases, in which specific proteins misfold, aggregate, and kill cells through proteotoxic stress. Heat shock protein levels may be increased or decreased in these disorders, with the direction of the response depending on the individual heat shock protein, the disease, cell type, and brain region. Aging is also associated with an accrual of proteotoxic stress and modulates expression of several heat shock proteins. We speculate that the increase in some heat shock proteins in neurodegenerative conditions may be partly responsible for the slow progression of these disorders, whereas the increase in some heat shock proteins with aging may help delay senescence. The protective nature of many heat shock proteins in experimental models of neurodegeneration supports these hypotheses. Furthermore, some heat shock proteins appear to be expressed at higher levels in longer-lived species. However, increases in heat shock proteins may be insufficient to override overwhelming proteotoxic stress or reverse the course of these conditions, because the expression of several other heat shock proteins and endogenous defense systems is lowered. In this review we describe a number of stressinduced changes in heat shock proteins as a function of age and neurodegenerative pathology, with an emphasis on the heat shock protein 70 (Hsp70) family and the two most common proteinopathic disorders of the brain, Alzheimer's and Parkinson's disease.

show abstract

Section: Heat Shock Proteins In Neurodegenerative Disorders and Agingmentioning

confidence: 99%

Heat shock proteins in neurodegenerative disorders and aging

Leak

2014

J. Cell Commun. Signal.

143

119

View full text Add to dashboard Cite

show abstract

“…The study showed a trend towards increased splicing of XBP1, with significantly increased levels of ATF4, pATF6 and CHOP, indicating activation of the PERK and ATF6 pathways and their culmination in apoptosis [108]. Overexpressed human -synuclein was found to associate with GRP78/BiP leading to its effective removal and prevention of neuronal apoptosis [108]. In addition to the proteasome and UPR, autophagy has been implicated in the degradation of -synuclein and PD pathogenesis [109,110].…”

Section: Proteotoxic Stress In the Pathogenesis Of Diseases Not Formementioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

View full text Add to dashboard Cite

Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

show abstract

“…ATF6 deficient animals exhibit increased ubiquitin positive inclusions and exacerbated dopaminergic neuron loss following MPTP treatment [91,92]. Overexpression of BiP using a gene therapy strategy also proved to be neuroprotective for dopaminergic neurons after overexpression of human α-synuclein in rats [93]. Finally, genetic ablation of proapoptotic CHOP/GADD153 has also been shown to be beneficial for dopaminergic neuronal survival following 6-OHDA but not after MPTP treatment, sustaining that UPR contribution in distinct PD models may be highly influenced by the chosen toxin for dopaminergic degeneration [7].…”

Section: Parkinson's Diseasementioning

confidence: 99%

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

Cabral‐Miranda

Hetz

2017

Endoplasmic Reticulum Stress in Diseases

View full text Add to dashboard Cite

The conception that protein aggregates composed by misfolded proteins underlies the occurrence of several neurodegenerative diseases suggests that this phenomenon may have a common origin, ultimately driven by disruption of proteostasis control. The unfolded protein response (UPR) embodies a major element of the proteostasis network, which is engaged by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as a possible mechanism of neurodegeneration, contributing to synaptic alterations, neuroinflammation and neuronal loss. In this review we discuss most recent findings relating ER stress and the development of distinct neurodegenerative diseases, and the possible strategies for disease intervention.

show abstract

Glucose Regulated Protein 78 Diminishes α-Synuclein Neurotoxicity in a Rat Model of Parkinson Disease

Cited by 157 publications

References 48 publications

Heat shock proteins in neurodegenerative disorders and aging

Heat shock proteins in neurodegenerative disorders and aging

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

Contact Info

Product

Resources

About