Cellular Mechanisms of Propagation and Clearance

Schätzl, Hermann

doi:10.1007/978-1-4614-5305-5_11

Cited by 2 publications

(3 citation statements)

References 85 publications

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“…Overall, the evidence outlined above suggests that enhanced autophagy acts as a clearance mechanism rather than a ‘seed-generating’ fragmentation mechanism. However, during our own work on autophagy, we found evidence for basal (i.e., non-induced) autophagy as a requirement for establishing prion-infection de novo [ 105 , 106 ]. In these studies, we exposed prion-susceptible and non-susceptible cultured cells to brain homogenates from non-infected or prion-infected mice.…”

Section: On the Biological Pathways That May Be Involved In The Frmentioning

confidence: 99%

From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins

2020

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Many devastating neurodegenerative diseases are driven by the misfolding of normal proteins into a pathogenic abnormal conformation. Examples of such protein misfolding diseases include Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. The misfolded proteins involved in these diseases form self-templating oligomeric assemblies that recruit further correctly folded protein and induce their conversion. Over time, this leads to the formation of high molecular and mostly fibrillar aggregates that are increasingly inefficient at converting normal protein. Evidence from a multitude of in vitro models suggests that fibrils are fragmented to form new seeds, which can convert further normal protein and also spread to neighboring cells as observed in vivo. While fragmentation and seed generation were suggested as crucial steps in aggregate formation decades ago, the biological pathways involved remain largely unknown. Here, we show that mechanisms of aggregate clearance—namely the mammalian Hsp70–Hsp40–Hsp110 tri-chaperone system, macro-autophagy, and the proteasome system—may not only be protective, but also play a role in fragmentation. We further review the challenges that exist in determining the precise contribution of these mechanisms to protein misfolding diseases and suggest future directions to resolve these issues.

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Section: On the Biological Pathways That May Be Involved In The Frmentioning

confidence: 99%

From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins

2020

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Section: Introductionmentioning

confidence: 99%

“…For acquired prion diseases, PrP Sc seeds are provided by the invading prions. In all three situations, the existing cellular clearance mechanisms dealing with aggregated proteins are bypassed or overwhelmed (Schatzl 2013;Marrero-Winkens et al 2020). When a certain threshold of PrP Sc seeds is exceeded, PrP Sc propagates in an autocatalytic process that increases the infectious load.…”

Section: Introductionmentioning

confidence: 99%

Vaccines for prion diseases: a realistic goal?

Napper

Schätzl

2023

Cell Tissue Res

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Prion diseases are fatal infectious neurodegenerative disorders and prototypic conformational diseases, caused by the conformational conversion of the normal cellular prion protein (PrPC) into the pathological PrPSc isoform. Examples are scrapie in sheep and goat, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids, and Creutzfeldt–Jacob disease (CJD) in humans. There are no therapies available, and animal prion diseases like BSE and CWD can negatively affect the economy, ecology, animal health, and possibly human health. BSE is a confirmed threat to human health, and mounting evidence supports the zoonotic potential of CWD. CWD is continuously expanding in North America in numbers and distribution and was recently identified in Scandinavian countries. CWD is the only prion disease occurring both in wild and farmed animals, which, together with extensive shedding of infectivity into the environment, impedes containment strategies. There is currently a strong push to develop vaccines against CWD, including ones that can be used in wildlife. The immune system does not develop a bona fide immune response against prion infection, as PrPC and PrPSc share an identical protein primary structure, and prions seem not to represent a trigger for immune responses. This asks for alternative vaccine strategies, which focus on PrPC-directed self-antibodies or exposure of disease-specific structures and epitopes. Several groups have established a proof-of-concept that such vaccine candidates can induce some levels of protective immunity in cervid and rodent models without inducing unwanted side effects. This review will highlight the most recent developments and discuss progress and challenges remaining.

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Cellular Mechanisms of Propagation and Clearance

Cited by 2 publications

References 85 publications

From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins

From Seeds to Fibrils and Back: Fragmentation as an Overlooked Step in the Propagation of Prions and Prion-Like Proteins

Vaccines for prion diseases: a realistic goal?

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