Faculty Opinions recommendation of Familial prion protein mutants inhibit Hrd1-mediated retrotranslocation of misfolded proteins by depleting misfolded protein sensor BiP.

2016 ◽  
Author(s):  
Karin Romisch
Keyword(s):  
Prion Protein ◽  
Misfolded Proteins ◽  
Misfolded Protein ◽  
Protein Mutants ◽  
Protein Sensor

scholarly journals Prion Diseases: A Unique Transmissible Agent or a Model for Neurodegenerative Diseases?

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 207
Author(s):  
Diane L. Ritchie ◽  
Marcelo A. Barria
Keyword(s):  
Public Health ◽  
Neurodegenerative Diseases ◽  
Prion Protein ◽  
Neurodegenerative Disorders ◽  
Prion Diseases ◽  
Experimental Models ◽  
Misfolded Proteins ◽  
Current Evidence

The accumulation and propagation in the brain of misfolded proteins is a pathological hallmark shared by many neurodegenerative diseases such as Alzheimer’s disease (Aβ and tau), Parkinson’s disease (α-synuclein), and prion disease (prion protein). Currently, there is no epidemiological evidence to suggest that neurodegenerative disorders are infectious, apart from prion diseases. However, there is an increasing body of evidence from experimental models to suggest that other pathogenic proteins such as Aβ and tau can propagate in vivo and in vitro in a prion-like mechanism, inducing the formation of misfolded protein aggregates such as amyloid plaques and neurofibrillary tangles. Such similarities have raised concerns that misfolded proteins, other than the prion protein, could potentially transmit from person-to-person as rare events after lengthy incubation periods. Such concerns have been heightened following a number of recent reports of the possible inadvertent transmission of Aβ pathology via medical and surgical procedures. This review will provide a historical perspective on the unique transmissible nature of prion diseases, examining their impact on public health and the ongoing concerns raised by this rare group of disorders. Additionally, this review will provide an insight into current evidence supporting the potential transmissibility of other pathogenic proteins associated with more common neurodegenerative disorders and the potential implications for public health.

scholarly journals Probing Early Misfolding Events in Prion Protein Mutants by NMR Spectroscopy

Molecules ◽  
2013 ◽  
Vol 18 (8) ◽  
pp. 9451-9476 ◽  
Author(s):  
Gabriele Giachin ◽  
Ivana Biljan ◽  
Gregor Ilc ◽  
Janez Plavec ◽  
Giuseppe Legname
Keyword(s):  
Nmr Spectroscopy ◽  
Prion Protein ◽  
Protein Mutants

scholarly journals Aggresomes: A Cellular Response to Misfolded Proteins

1998 ◽  
Vol 143 (7) ◽  
pp. 1883-1898 ◽  
Author(s):  
Jennifer A. Johnston ◽  
Cristina L. Ward ◽  
Ron R. Kopito
Keyword(s):  
Cellular Response ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Integral Membrane Protein ◽  
Misfolded Proteins ◽  
Intermediate Filament Protein ◽  
Misfolded Protein ◽  
Cytoplasmic Inclusions ◽  
Aggresome Formation ◽  
General Response

Intracellular deposition of misfolded protein aggregates into ubiquitin-rich cytoplasmic inclusions is linked to the pathogenesis of many diseases. Why these aggregates form despite the existence of cellular machinery to recognize and degrade misfolded protein and how they are delivered to cytoplasmic inclusions are not known. We have investigated the intracellular fate of cystic fibrosis transmembrane conductance regulator (CFTR), an inefficiently folded integral membrane protein which is degraded by the cytoplasmic ubiquitin-proteasome pathway. Overexpression or inhibition of proteasome activity in transfected human embryonic kidney or Chinese hamster ovary cells led to the accumulation of stable, high molecular weight, detergent-insoluble, multiubiquitinated forms of CFTR. Using immunofluorescence and transmission electron microscopy with immunogold labeling, we demonstrate that undegraded CFTR molecules accumulate at a distinct pericentriolar structure which we have termed the aggresome. Aggresome formation is accompanied by redistribution of the intermediate filament protein vimentin to form a cage surrounding a pericentriolar core of aggregated, ubiquitinated protein. Disruption of microtubules blocks the formation of aggresomes. Similarly, inhibition of proteasome function also prevented the degradation of unassembled presenilin-1 molecules leading to their aggregation and deposition in aggresomes. These data lead us to propose that aggresome formation is a general response of cells which occurs when the capacity of the proteasome is exceeded by the production of aggregation-prone misfolded proteins.

scholarly journals Novel dominant-negative prion protein mutants identified from a randomized library

2008 ◽  
Vol 21 (10) ◽  
pp. 623-629 ◽  
Author(s):  
David Ott ◽  
Cornelia Taraborrelli ◽  
Adriano Aguzzi
Keyword(s):  
Prion Protein ◽  
Dominant Negative ◽  
Protein Mutants

scholarly journals Ubiquitin conjugation triggers misfolded protein sequestration into quality control foci when Hsp70 chaperone levels are limiting

2013 ◽  
Vol 24 (13) ◽  
pp. 2076-2087 ◽  
Author(s):  
Ayala Shiber ◽  
William Breuer ◽  
Michael Brandeis ◽  
Tommer Ravid
Keyword(s):  
Quality Control ◽  
Heat Shock Protein 70 ◽  
Inclusion Bodies ◽  
Amyloid Plaques ◽  
Model System ◽  
Misfolded Proteins ◽  
Misfolded Protein ◽  
Pathological Conditions ◽  
Hsp70 Chaperone ◽  
Ubiquitin Conjugation

Ubiquitin accumulation in amyloid plaques is a pathological marker observed in the vast majority of neurodegenerative diseases, yet ubiquitin function in these inclusions is controversial. It has been suggested that ubiquitylated proteins are directed to inclusion bodies under stress conditions, when both chaperone-mediated refolding and proteasomal degradation are compromised or overwhelmed. Alternatively, ubiquitin and chaperones may be recruited to preformed inclusions to promote their elimination. We address this issue using a yeast model system, based on expression of several mildly misfolded degradation substrates in cells with altered chaperone content. We find that the heat shock protein 70 (Hsp70) chaperone pair Ssa1/Ssa2 and the Hsp40 cochaperone Sis1 are essential for degradation. Substrate ubiquitylation is strictly dependent on Sis1, whereas Ssa1 and Ssa2 are dispensable. Remarkably, in Ssa1/Ssa2-depleted cells, ubiquitylated substrates are sequestered into detergent-insoluble, Hsp42-positive inclusion bodies. Unexpectedly, sequestration is abolished by preventing substrate ubiquitylation. We conclude that Hsp40 is required for the targeting of misfolded proteins to the ubiquitylation machinery, whereas the decision to degrade or sequester ubiquitylated proteins is mediated by the Hsp70s. Accordingly, diminished Hsp70 levels, as observed in aging or certain pathological conditions, might be sufficient to trigger ubiquitin-dependent sequestration of partially misfolded proteins into inclusion bodies.

scholarly journals Defective Retrotranslocation Causes Loss of Anti-Bax Function in Human Familial Prion Protein Mutants

2007 ◽  
Vol 27 (19) ◽  
pp. 5081-5091 ◽  
Author(s):  
J. Jodoin ◽  
S. Laroche-Pierre ◽  
C. G. Goodyer ◽  
A. C. LeBlanc
Keyword(s):  
Prion Protein ◽  
Protein Mutants

scholarly journals Mechanisms of Aggresome Biogenesis: Ubiquitination, Transport, & Maintenance

2019 ◽  
Author(s):  
AJ Keefe
Keyword(s):  
Intermediate Filament ◽  
Retrograde Transport ◽  
Regulatory Proteins ◽  
Misfolded Proteins ◽  
Misfolded Protein ◽  
Proteotoxic Stress ◽  
Organizing Center ◽  
Critical Insight ◽  
Insight Into ◽  
Do So

Neurodegenerative diseases are universally marked by the accumulation of misfolded protein. Neurons respond to these proteostatic disturbances by sequestering, and thus inactivating, toxic misfolded proteins into a perinuclear organelle called the aggresome. The aggresome can be subsequently degraded in bulk by autophagy, a process termed aggrephagy. The formation of protein aggregates has historically been considered a spontaneous and unregulated process, but emerging research has instead discovered a diverse cohort of regulatory proteins that mediate protein aggregation. Chaperones are the first proteins to respond to misfolded proteins, and do so by recognizing the aberrant exposure of hydrophobic domains. When chaperones are unable to correctly refold proteins, their substrates are  transferred to ubiquitin ligating machinery to catalyze polyubiquitination. Although ubiquitin chains typically direct proteins towards proteasomes, severe proteotoxic stress can overwhelm, or even directly inhibit, proteasomes. As an alternative to proteasomal degradation, misfolded proteins are redirected towards the mitotic organizing center (MTOC) and, following retrograde transport by dynein, are packaged and sequestered within an intermediate filament (IF) cage to form the aggresome. The biogenesis of the aggresome is thus a highly regulated event, and a better understanding of the mechanisms facilitating this process will provide critical insight into neurodegenerative disease.

scholarly journals Endoplasmic reticulum tubules limit the size of misfolded protein condensates

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Smriti Parashar ◽  
Ravi Chidambaram ◽  
Shuliang Chen ◽  
Christina R Liem ◽  
Eric Griffis ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Misfolded Proteins ◽  
Type I ◽  
Misfolded Protein ◽  
Substrate Type ◽  
Knock Out ◽  
Type I Procollagen ◽  
Long Form

The endoplasmic reticulum (ER) is composed of sheets and tubules. Here we report that the COPII coat subunit, SEC24C, works with the long form of the tubular ER-phagy receptor, RTN3, to target dominant-interfering mutant proinsulin Akita puncta to lysosomes. When the delivery of Akita puncta to lysosomes was disrupted, large puncta accumulated in the ER. Unexpectedly, photobleach analysis indicated that Akita puncta behaved as condensates and not aggregates, as previously suggested. Akita puncta enlarged when either RTN3 or SEC24C were depleted, or when ER sheets were proliferated by either knocking out Lunapark or overexpressing CLIMP63. Other ER-phagy substrates that are segregated into tubules behaved like Akita, while a substrate (type I procollagen) that is degraded by the ER-phagy sheets receptor, FAM134B, did not. Conversely, when ER tubules were augmented in Lunapark knock-out cells by overexpressing reticulons, ER-phagy increased and the number of large Akita puncta was reduced. Our findings imply that segregating cargoes into tubules has two beneficial roles. First, it localizes mutant misfolded proteins, the receptor, and SEC24C to the same ER domain. Second, physically restraining condensates within tubules, before they undergo ER-phagy, prevents them from enlarging and impacting cell health.

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